Ertl, C.
Ruf, T.
Mentzer, D.
Kong, M.
Kramer, R.
Bergwelt-Baildon, M.V.
Subklewe, M.
Tomsitz, D.
Ascierto, P.A.
Dummer, R.
Gogas, H.
Lebbé, C.
Long, G.V.
McArthur, G.
Neilan, T.G.
Ribas, A.
Robert, C.
Schadendorf, D.
Zimmer, L.
Eigentler, T.
Grabbe, S.
Forschner, A.
Kähler, K.C.
Milani, V.
Pföhler, C.
Hassel, J.
Gutzmer, R.
Loquai, C.
Routy, B.
Furness, A.J.
Blank, C.
Wolchok, J.D.
French, L.E.
Hauschild, A.
Heinzerling, L.
(2024). The side effect registry immuno-oncology (SERIO) – A tool for systematic analysis of immunotherapy-induced side effects. European journal of cancer,
Vol.199,
pp. 113505-113505.
Bai, X.
Shaheen, A.
Grieco, C.
d'Arienzo, P.D.
Mina, F.
Czapla, J.A.
Lawless, A.R.
Bongiovanni, E.
Santaniello, U.
Zappi, H.
Dulak, D.
Williamson, A.
Lee, R.
Gupta, A.
Li, C.
Si, L.
Ubaldi, M.
Yamazaki, N.
Ogata, D.
Johnson, R.
Park, B.C.
Jung, S.
Madonna, G.
Hochherz, J.
Umeda, Y.
Nakamura, Y.
Gebhardt, C.
Festino, L.
Capone, M.
Ascierto, P.A.
Johnson, D.B.
Lo, S.N.
Long, G.V.
Menzies, A.M.
Namikawa, K.
Mandala, M.
Guo, J.
Lorigan, P.
Najjar, Y.G.
Haydon, A.
Quaglino, P.
Boland, G.M.
Sullivan, R.J.
Furness, A.J.
Plummer, R.
Flaherty, K.T.
(2024). Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study. Eclinicalmedicine,
Vol.71,
p. 102564.
full text
Spain, L.
Coulton, A.
Lobon, I.
Rowan, A.
Schnidrig, D.
Shepherd, S.T.
Shum, B.
Byrne, F.
Goicoechea, M.
Piperni, E.
Au, L.
Edmonds, K.
Carlyle, E.
Hunter, N.
Renn, A.
Messiou, C.
Hughes, P.
Nobbs, J.
Foijer, F.
van den Bos, H.
Wardenaar, R.
Spierings, D.C.
Spencer, C.
Schmitt, A.M.
Tippu, Z.
Lingard, K.
Grostate, L.
Peat, K.
Kelly, K.
Sarker, S.
Vaughan, S.
Mangwende, M.
Terry, L.
Kelly, D.
Biano, J.
Murra, A.
Korteweg, J.
Lewis, C.
O'Flaherty, M.
Cattin, A.-.
Emmerich, M.
Gerard, C.L.
Pallikonda, H.A.
Lynch, J.
Mason, R.
Rogiers, A.
Xu, H.
Huebner, A.
McGranahan, N.
Al Bakir, M.
Murai, J.
Naceur-Lombardelli, C.
Borg, E.
Mitchison, M.
Moore, D.A.
Falzon, M.
Proctor, I.
Stamp, G.W.
Nye, E.L.
Young, K.
Furness, A.J.
Pickering, L.
Stewart, R.
Mahadeva, U.
Green, A.
Larkin, J.
Litchfield, K.
Swanton, C.
Jamal-Hanjani, M.
PEACE Consortium,
Turajlic, S.
(2023). Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways. Cancer discov,
Vol.13
(6),
pp. 1364-1385.
show abstract
full text
UNLABELLED: Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275..
Julve, M.
Furness, A.J.
(2023). Advances in the development of tumor-infiltrating lymphocyte therapy for advanced melanoma. Expert opinion on biological therapy,
Vol.23
(4),
pp. 319-323.
Linardou, H.
Adjei, A.A.
Bajpai, J.
Banerjee, S.
Berghoff, A.S.
Mathias, C.C.
Choo, S.P.
Dent, R.
Felip, E.
Furness, A.J.
Garassino, M.C.
Garralda, E.
Konsoulova-Kirova, A.
Letsch, A.
Menzies, A.M.
Mukherji, D.
Peters, S.
Sessa, C.
Tsang, J.
Yang, J.C.
Garrido, P.
(2023). Challenges in oncology career: are we closing the gender gap? Results of the new ESMO Women for Oncology Committee survey. Esmo open,
Vol.8
(2),
p. 100781.
show abstract
full text
BACKGROUND: Following a European Society for Medical Oncology Women for Oncology (ESMO W4O) survey in 2016 showing severe under-representation of female oncologists in leadership roles, ESMO launched a series of initiatives to address obstacles to gender equity. A follow-up survey in October 2021 investigated progress achieved. MATERIALS AND METHODS: The W4O questionnaire 2021 expanded on the 2016 survey, with additional questions on the impact of ethnicity, sexual orientation and religion on career development. Results were analysed according to respondent gender and age. RESULTS: The survey sample was larger than in 2016 (n = 1473 versus 482), especially among men. Significantly fewer respondents had managerial or leadership roles than in 2016 (31.8% versus 51.7%). Lack of leadership development for women and unconscious bias were considered more important in 2021 than in 2016. In 2021, more people reported harassment in the workplace than in 2016 (50.3% versus 41.0%). In 2021, ethnicity, sexual orientation and religion were considered to have little or no impact on professional career opportunities, salary setting or related potential pay gap. However, gender had a significant or major impact on career development (25.5% of respondents), especially in respondents ≤40 years of age and women. As in 2016, highest ranked initiatives to foster workplace equity were promotion of work-life balance, development and leadership training and flexible working. Significantly more 2021 respondents (mainly women) supported the need for culture and gender equity education at work than in 2016. CONCLUSIONS: Gender remains a major barrier to career progression in oncology and, although some obstacles may have been reduced since 2016, we are a long way from closing the gender gap. Increased reporting of discrimination and inappropriate behaviour in the workplace is a major, priority concern. The W4O 2021 survey findings provide new evidence and highlight the areas for future ESMO interventions to support equity and diversity in oncology career development..
Manacorda, S.
Carmena, M.D.
Malone, C.
Linh Le, H.M.
Furness, A.J.
Larkin, J.
Schmitt, A.M.
(2023). Ipilimumab plus nivolumab in patients with symptomatic melanoma brain metastasis requiring corticosteroids. Eur j cancer,
Vol.188,
pp. 98-107.
show abstract
STUDY AIM: To investigate the efficacy of PD-1-directed antibody-based therapy in patients with symptomatic melanoma brain metastases (MBM) and concurrent treatment with corticosteroids. METHODS: This retrospective cohort study included patients with cutaneous melanoma with symptomatic MBM and concurrent treatment with corticosteroids who received PD-1-directed antibody-based treatment at the Royal Marsden Hospital London between 2016 and 2021. The primary outcome was overall survival (OS), secondary outcomes were intracranial response rate (ORR) and duration of response (DOR). We used the Kaplan-Meier method to describe survival. RESULTS: Between 2016 and 2021, 256 patients presented with metastatic melanoma, of whom 29 were eligible with symptomatic MBM requiring corticosteroids and receiving ipilimumab plus nivolumab. Median age was 54 (interquartile range 44, 66). Median OS was 5.45months (95% confidence interval (CI) 2.89, 29.40), with 21% of patients (95% CI 9%, 47%) alive after 3years. ORR was 28% (8/29) and DOR was 7.85months (95% CI 7.85, not estimably [NE]). Responding patients had a median OS of 56.4months (95% CI 46.03, NE). Elevated lactate dehydrogenase and Eastern Cooperative Oncology Group PS> 2 were associated with poorer outcomes (median OS 29.4 versus 3.12months and 6.44 versus 5.13months), no such association was observed for corticosteroid dose, number of lesions, or line of treatment. CONCLUSION: Patients with symptomatic MBM derive only modest benefit from combination immunotherapy treatment. Nevertheless, those with disease response have the potential to derive long-term benefit, justifying ipilimumab plus nivolumab in this group in the absence of other more effective treatment options..
Wu, M.Y.
Shepherd, S.T.
Fendler, A.
Carr, E.J.
Au, L.
Harvey, R.
Dowgier, G.
Hobbs, A.
Herman, L.S.
Ragno, M.
Adams, L.
Schmitt, A.M.
Tippu, Z.
Shum, B.
Farag, S.
Rogiers, A.
O'Reilly, N.
Bawumia, P.
Smith, C.
Carlyle, E.
Edmonds, K.
Del Rosario, L.
Lingard, K.
Mangwende, M.
Holt, L.
Ahmod, H.
Korteweg, J.
Foley, T.
Barber, T.
Hepworth, S.
Emslie-Henry, A.
Caulfield-Lynch, N.
Byrne, F.
Deng, D.
Williams, B.
Brown, M.
Caidan, S.
Gavrielides, M.
MacRae, J.I.
Kelly, G.
Peat, K.
Kelly, D.
Murra, A.
Kelly, K.
O'Flaherty, M.
Popat, S.
Yousaf, N.
Jhanji, S.
Tatham, K.
Cunningham, D.
Van As, N.
Young, K.
Furness, A.J.
Pickering, L.
Beale, R.
Swanton, C.
Gandhi, S.
Gamblin, S.
Bauer, D.L.
Kassiotis, G.
Howell, M.
Walker, S.
Nicholson, E.
Larkin, J.
Wall, E.C.
Turajlic, S.
CAPTURE consortium,
(2023). Sotrovimab restores neutralization against current Omicron subvariants in patients with blood cancer. Cancer cell,
Vol.41
(5),
pp. 821-823.
show abstract
full text
Wu et al. report that patients with hematologic malignancies have reduced immunity against SARS-CoV-2 Omicron subvariants and Sotrovimab retains neutralizing capacity against all tested Omicron subvariants..
Bai, X.
Shaheen, A.
Grieco, C.
d'Arienzo, P.D.
Mina, F.
Czapla, J.A.
Lawless, A.R.
Bongiovanni, E.
Santaniello, U.
Zappi, H.
Dulak, D.
Williamson, A.
Lee, R.
Gupta, A.
Li, C.
Si, L.
Ubaldi, M.
Yamazaki, N.
Ogata, D.
Johnson, R.
Park, B.C.
Jung, S.
Madonna, G.
Hochherz, J.
Umeda, Y.
Nakamura, Y.
Gebhardt, C.
Festino, L.
Capone, M.
Ascierto, P.A.
Johnson, D.B.
Lo, S.N.
Long, G.V.
Menzies, A.M.
Namikawa, K.
Mandala, M.
Guo, J.
Lorigan, P.
Najjar, Y.G.
Haydon, A.
Quaglino, P.
Boland, G.M.
Sullivan, R.J.
Furness, A.J.
Plummer, R.
Flaherty, K.T.
(2023). Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study. Eclinicalmedicine,
Vol.65,
p. 102290.
show abstract
full text
BACKGROUND: Both dabrafenib/trametinib (D/T) and anti-PD-1 monotherapy (PD-1) are approved adjuvant therapies for patients with stage III BRAF V600-mutant melanoma. However, there is still a lack of head-to-head comparative data. We aimed to describe efficacy and toxicity outcomes for these two standard therapies across melanoma centers. METHODS: This multicenter, retrospective cohort study was conducted in 15 melanoma centers in Australia, China, Germany, Italy, Japan, UK, and US. We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1 between Jul 2015 and Oct 2022. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), recurrence pattern and toxicity. FINDINGS: We included 598 patients with stage III BRAF V600-mutant melanoma who received either adjuvant D/T (n = 393 [66%]) or PD-1 (n = 205 [34%]) post definitive surgery between Jul 2015 and Oct 2022. At a median follow-up of 33 months (IQR 21-43), the median RFS was 51.0 months (95% CI 41.0-not reached [NR]) in the D/T group, significantly longer than PD-1 (44.8 months [95% CI 28.5-NR]) (univariate: HR 0.66, 95% CI 0.50-0.87, P = 0.003; multivariate: HR 0.58, 95% CI 0.39-0.86, P = 0.007), with comparable OS with PD-1 (multivariate, HR 0.90, 95% CI 0.48-1.70, P = 0.75). Similar findings were observed using a restricted-mean-survival-time model. Among those who experienced recurrence, the proportion of distant metastases was higher in the D/T cohort. D/T had a higher incidence of treatment modification due to adverse events (AEs) than PD-1, but fewer persistent AEs. INTERPRETATION: In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS. D/T seems to provide a better outcome compared with PD-1, but a longer follow-up and ideally a large prospective trial are needed. FUNDING: Dr. Xue Bai was supported by the Beijing Hospitals Authority Youth Programme (QMS20211101) for her efforts devoted to this study. Dr. Keith T. Flaherty was funded by Adelson Medical Research Foundation for the efforts devoted to this study..
Safian, D.
Ahmed, M.
van Kruistum, H.
Furness, A.I.
Reznick, D.N.
Wiegertjes, G.F.
Pollux, B.J.
(2023). Repeated independent origins of the placenta reveal convergent and divergent organ evolution within a single fish family (Poeciliidae). Sci adv,
Vol.9
(34),
p. eadf3915.
show abstract
full text
An outstanding question in biology is to what extent convergent evolution produces similar, but not necessarily identical, complex phenotypic solutions. The placenta is a complex organ that repeatedly evolved in the livebearing fish family Poeciliidae. Here, we apply comparative approaches to test whether evolution has produced similar or different placental phenotypes in the Poeciliidae and to what extent these phenotypes correlate with convergence at the molecular level. We show the existence of two placental phenotypes characterized by distinctly different anatomical adaptations (divergent evolution). Furthermore, each placental phenotype independently evolved multiple times across the family, providing evidence for repeated convergence. Moreover, our comparative genomic analysis revealed that the genomes of species with different placentas are evolving at a different pace. Last, we show that the two placental phenotypes correlate with two previously described contrasting life-history optima. Our results argue for high evolvability (both divergent and convergent) of the placenta within a group of closely related species in a single family..
Fu, X.
Zhao, Y.
Lopez, J.I.
Rowan, A.
Au, L.
Fendler, A.
Hazell, S.
Xu, H.
Horswell, S.
Shepherd, S.T.
Spencer, C.E.
Spain, L.
Byrne, F.
Stamp, G.
O'Brien, T.
Nicol, D.
Augustine, M.
Chandra, A.
Rudman, S.
Toncheva, A.
Furness, A.J.
Pickering, L.
Kumar, S.
Koh, D.-.
Messiou, C.
Dafydd, D.A.
Orton, M.R.
Doran, S.J.
Larkin, J.
Swanton, C.
Sahai, E.
Litchfield, K.
Turajlic, S.
TRACERx Renal Consortium,
Bates, P.A.
(2022). Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study. Nat ecol evol,
Vol.6
(1),
pp. 88-102.
show abstract
full text
Genetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal diversification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal diversification, enabling interpretation of clonal diversity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and microdiversity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal diversification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution..
Mahalingam, P.
Julve, M.
Huang, P.
Furness, A.J.
Pollack, S.M.
Jones, R.L.
(2022). Immunotherapy of sarcomas with modified T cells. Curr opin oncol,
Vol.34
(4),
pp. 362-370.
show abstract
full text
PURPOSE OF REVIEW: To summarize the development of modified T-cell therapies in sarcomas and discuss relevant published and ongoing clinical trials to date. RECENT FINDINGS: Numerous clinical trials are underway evaluating tumor-specific chimeric antigen receptor T cells and high affinity T-cell receptor (TCR)-transduced T cells in sarcomas. Notably, translocation-dependent synovial sarcoma and myxoid/round cell liposarcoma are the subject of several phase II trials evaluating TCRs targeting cancer testis antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and melanoma antigen-A4 (MAGE A4), and response rates of up to 60% have been observed for NY-ESO-1 directed, modified T cells in synovial sarcoma. Challenges posed by modified T-cell therapy include limitations conferred by HLA-restriction, non-immunogenic tumor microenvironments (TME), aggressive lymphodepletion and immune-mediated toxicities restricting coinfusion of cytokines. SUMMARY: Cellular therapy to augment the adaptive immune response through delivery of modified T cells is an area of novel therapeutic development in sarcomas where a reliably expressed, ubiquitous target antigen can be identified. Therapeutic tools to improve the specificity, signaling, proliferation and persistence of modified TCRs and augment clinical responses through safe manipulation of the sarcoma TME will be necessary to harness the full potential of this approach..
Furness, A.I.
Venditti, C.
Capellini, I.
(2022). Terrestrial reproduction and parental care drive rapid evolution in the trade-off between offspring size and number across amphibians. Plos biol,
Vol.20
(1),
p. e3001495.
show abstract
full text
The trade-off between offspring size and number is central to life history strategies. Both the evolutionary gain of parental care or more favorable habitats for offspring development are predicted to result in fewer, larger offspring. However, despite much research, it remains unclear whether and how different forms of care and habitats drive the evolution of the trade-off. Using data for over 800 amphibian species, we demonstrate that, after controlling for allometry, amphibians with direct development and those that lay eggs in terrestrial environments have larger eggs and smaller clutches, while different care behaviors and adaptations vary in their effects on the trade-off. Specifically, among the 11 care forms we considered at the egg, tadpole and juvenile stage, egg brooding, male egg attendance, and female egg attendance increase egg size; female tadpole attendance and tadpole feeding decrease egg size, while egg brooding, tadpole feeding, male tadpole attendance, and male tadpole transport decrease clutch size. Unlike egg size that shows exceptionally high rates of phenotypic change in just 19 branches of the amphibian phylogeny, clutch size has evolved at exceptionally high rates in 135 branches, indicating episodes of strong selection; egg and tadpole environment, direct development, egg brooding, tadpole feeding, male tadpole attendance, and tadpole transport explain 80% of these events. By explicitly considering diversity in parental care and offspring habitat by stage of offspring development, this study demonstrates that more favorable conditions for offspring development promote the evolution of larger offspring in smaller broods and reveals that the diversity of parental care forms influences the trade-off in more nuanced ways than previously appreciated..
Dekker, M.L.
van Son, L.M.
Leon-Kloosterziel, K.M.
Hagmayer, A.
Furness, A.I.
van Leeuwen, J.L.
Pollux, B.J.
(2022). Multiple paternity in superfetatious live-bearing fishes. J evol biol,
Vol.35
(7),
pp. 948-961.
show abstract
full text
Superfetation, the ability to carry several overlapping broods at different developmental stages, has evolved independently multiple times within the live-bearing fish family Poeciliidae. Even though superfetation is widespread among poeciliids, its evolutionary advantages remain unclear. Theory predicts that superfetation should increase polyandry by increasing the probability that temporally overlapping broods are fertilized by different fathers. Here, we test this key prediction in two poeciliid species that each carry two temporally overlapping broods: Poeciliopsis retropinna and P. turrubarensis. We collected 25 females per species from freshwater streams in South-Eastern Costa Rica and assessed multiple paternity by genotyping all their embryos (420 embryos for P. retropinna; 788 embryos for P. turrubarensis) using existing and newly developed microsatellite markers. We observed a high frequency of unique sires in the simultaneous, temporally overlapping broods in P. retropinna (in 56% of the pregnant females) and P. turrubarensis (79%). We found that the mean number of sires within females was higher than the number of sires within the separate broods (2.92 sires within mothers vs. 2.36 within separate broods in P. retropinna; and 3.40 vs 2.56 in P. turrubarensis). We further observed that there were significant differences in the proportion of offspring sired by each male in 42% of pregnant female P. retropinna and 65% of female P. turrubarensis; however, this significance applied to only 9% and 46% of the individual broods in P. retropinna and P. turrubarensis, respectively, suggesting that the unequal reproductive success of sires (i.e. reproductive skew) mostly originated from differences in paternal contribution between, rather than within broods. Together, these findings tentatively suggest that superfetation may promote polyandry and reproductive skew in live-bearing fishes..
Alexander, J.L.
Ibraheim, H.
Richards, C.
Shum, B.
Pavlidis, P.
Hunter, N.
Teare, J.P.
Wotherspoon, A.
Furness, A.
Turajlic, S.
Pickering, L.
Larkin, J.
Speight, A.
Papa, S.
Powell, N.
(2022). Oral beclomethasone dipropionate is an effective treatment for immune checkpoint inhibitor induced colitis. J immunother cancer,
Vol.10
(9).
show abstract
full text
INTRODUCTION: Systemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. We hypothesized that BD would be an effective treatment for CPI-induced colitis. METHODS: We performed a retrospective analysis of all patients who started BD for CPI-induced colitis at three UK cancer centers between November 2017 and October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5 mg once daily for 28 days. Data were collected from electronic patient records. Clinical outcomes were assessed at 28 days after initiation of treatment. RESULTS: Twenty-two patients (14 male) with a median age of 64 (range 45-84) with CPI-induced colitis were treated with BD. At baseline, the median number of loose stools in a 24-hour period was six (common terminology criteria for adverse events, CTCAE grade diarrhea=2). Thirteen patients (59%) were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed moderate inflammation (Mayo Endoscopic Score (MES) = 2) in two patients (9%), mild inflammation (MES=1) in nine patients (41%) and normal findings (MES=0) in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. All 22 patients (100%) had a clinical response to BD and 21 (95%) achieved clinical remission with a return to baseline stool frequency (CTCAE diarrhea=0). Ten patients (45%) had symptomatic relapse on cessation of BD, half within 7 days of stopping. All patients recaptured response on restarting BD. No adverse events were reported in patients treated with BD. CONCLUSIONS: Topical BD represents an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was effective and safe at inducing remission in CPI-induced colitis, which was refractory to systemic corticosteroids. Further randomized studies are needed to confirm these findings and determine the optimum dosing regimen..
Furness, A.I.
Capellini, I.
(2022). The reproductive ecology drivers of egg attendance in amphibians. Ecol lett,
Vol.25
(11),
pp. 2500-2512.
show abstract
full text
Parental care is extremely diverse but, despite much research, why parental care evolves is poorly understood. Here we address this outstanding question using egg attendance, the simplest and most common care form in many taxa. We demonstrate that, in amphibians, terrestrial egg deposition, laying eggs in hidden locations and direct development promote the evolution of female egg attendance. Male egg attendance follows the evolution of hidden eggs and is associated with terrestrial egg deposition but not with direct development. We conclude that egg attendance, particularly by females, evolves following changes in reproductive ecology that are likely to increase egg survival, select for small clutches of large eggs and/or expose eggs to new environmental challenges. While our results resolve a long-standing question on whether reproductive ecology traits are drivers, consequences or alternative solutions to caring, they also unravel important, yet previously unappreciated, differences between the sexes..
Pettinger, C.
Livings, C.
Grochot, R.
Furness, A.
Lopez, J.
(2022). 'You give me fever!': are health services ready for immune cell engager therapy in advanced solid malignancies?. J immunother cancer,
Vol.10
(12).
show abstract
full text
Immune cell engager therapeutic strategies using bioengineered molecules to redirect immune cells into tumor are starting to demonstrate promising clinical activity in multiple early phase trials across numerous targets and a range of solid tumor types. These therapies, however, carry the risk of exaggerated cytokine-mediated on-target off-tumor adverse events that require highly specialized inpatient facilities. We report here the Royal Marsden experience of treating patients with advanced solid tumors on early phase immune engager clinical trials in a dedicated inpatient facility, focusing specifically on patterns of cytokine-mediated toxicity seen and proposing a risk-mitigation algorithm for the safe, feasible and scalable delivery of these therapies..
Chesney, J.
Lewis, K.D.
Kluger, H.
Hamid, O.
Whitman, E.
Thomas, S.
Wermke, M.
Cusnir, M.
Domingo-Musibay, E.
Phan, G.Q.
Kirkwood, J.M.
Hassel, J.C.
Orloff, M.
Larkin, J.
Weber, J.
Furness, A.J.
Khushalani, N.I.
Medina, T.
Egger, M.E.
Graf Finckenstein, F.
Jagasia, M.
Hari, P.
Sulur, G.
Shi, W.
Wu, X.
Sarnaik, A.
(2022). Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J immunother cancer,
Vol.10
(12).
show abstract
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BACKGROUND: Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma. METHODS: Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1). RESULTS: The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD
Fendler, A.
Shepherd, S.T.
Au, L.
Wu, M.
Harvey, R.
Wilkinson, K.A.
Schmitt, A.M.
Tippu, Z.
Shum, B.
Farag, S.
Rogiers, A.
Carlyle, E.
Edmonds, K.
Del Rosario, L.
Lingard, K.
Mangwende, M.
Holt, L.
Ahmod, H.
Korteweg, J.
Foley, T.
Barber, T.
Emslie-Henry, A.
Caulfield-Lynch, N.
Byrne, F.
Deng, D.
Kjaer, S.
Song, O.-.
Queval, C.J.
Kavanagh, C.
Wall, E.C.
Carr, E.J.
Caidan, S.
Gavrielides, M.
MacRae, J.I.
Kelly, G.
Peat, K.
Kelly, D.
Murra, A.
Kelly, K.
O'Flaherty, M.
Shea, R.L.
Gardner, G.
Murray, D.
Popat, S.
Yousaf, N.
Jhanji, S.
Tatham, K.
Cunningham, D.
Van As, N.
Young, K.
Furness, A.J.
Pickering, L.
Beale, R.
Swanton, C.
Gandhi, S.
Gamblin, S.
Bauer, D.L.
Kassiotis, G.
Howell, M.
Nicholson, E.
Walker, S.
Wilkinson, R.J.
Larkin, J.
Turajlic, S.
(2022). Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer. Cell rep med,
Vol.3
(10),
p. 100781.
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Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination..
Andres, M.S.
Ramalingam, S.
Rosen, S.D.
Baksi, J.
Khattar, R.
Kirichenko, Y.
Young, K.
Yousaf, N.
Okines, A.
Huddart, R.
Harrington, K.
Furness, A.J.
Turajlic, S.
Pickering, L.
Popat, S.
Larkin, J.
Lyon, A.R.
(2022). The spectrum of cardiovascular complications related to immune-checkpoint inhibitor treatment : Including myocarditis and the new entity of non inflammatory left ventricular dysfunction. Cardiooncology,
Vol.8
(1),
p. 21.
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BACKGROUND: The full range of cardiovascular complications related to the use of Immune checkpoint inhibitors (ICI) is not fully understood. We aim to describe the spectrum of cardiovascular adverse events (cvAEs) by presenting our real-world experience of the diagnosis and management of these complications. METHODS: Two thousand six hundred and forty-seven (2647) patients were started on ICI treatment between 2014 and 2020. Data from 110 patients referred to the cardio-oncology service with a suspected cvAE was collected prospectively and analysed. RESULTS: Eighty-nine patients (3.4%) were confirmed to have cvAEs while on ICI therapy. Myocarditis was the most frequent event (33/89), followed by tachyarrhythmia (27/89), non-inflammatory left ventricular dysfunction (NILVD) (15/89) and pericarditis (7/89). Results from myocarditis and non-inflammatory left ventricular dysfunction cohorts were compared. Myocarditis and NILVD showed significant differences in respect toof troponin elevation, cardiac magnetic resonance abnormalities and ventricular function. Dual ICI therapy and other immune related adverse events were more frequently associated with myocarditis than NILVD. There was a significant difference in the median time from starting ICI treatment to presentation with myocarditis versus NILVD (12 vs 26 weeks p = 0.049). Through early recognition of myocarditis, prompt treatment with steroids and interruption of ICI, there were no cardiovascular in-hospital deaths. NILVD did not require steroid treatment and ICI could be restarted safely. CONCLUSIONS: The full spectrum of cardiovascular complications in patients with immune checkpoint inhibitors is much broader than initially described. Myocarditis remains the most frequent cvAE related to ICI treatment. A novel type of myocardial injury was observed and defined as Atrial tachyarrhythmias and NILVD were also frequent in this cohort. NILVD has a This differs fromdifferent presentation from ICI-related myocarditis, mainly usually presenting afterby the lack of inflammatory features on CMR and biomarkers and a later presentation in time..
Litchfield, K.
Reading, J.L.
Puttick, C.
Thakkar, K.
Abbosh, C.
Bentham, R.
Watkins, T.B.
Rosenthal, R.
Biswas, D.
Rowan, A.
Lim, E.
Al Bakir, M.
Turati, V.
Guerra-Assunção, J.A.
Conde, L.
Furness, A.J.
Saini, S.K.
Hadrup, S.R.
Herrero, J.
Lee, S.-.
Van Loo, P.
Enver, T.
Larkin, J.
Hellmann, M.D.
Turajlic, S.
Quezada, S.A.
McGranahan, N.
Swanton, C.
(2021). Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell,
Vol.184
(3),
pp. 596-614.e14.
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Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity..
Garrido, P.
Adjei, A.A.
Bajpai, J.
Banerjee, S.
Berghoff, A.S.
Choo, S.P.
Felip, E.
Furness, A.J.
Garralda, E.
Haanen, J.
Letsch, A.
Linardou, H.
Peters, S.
Sessa, C.
Tabernero, J.
Tsang, J.
Yang, J.C.
Garassino, M.C.
(2021). Has COVID-19 had a greater impact on female than male oncologists? Results of the ESMO Women for Oncology (W4O) Survey. Esmo open,
Vol.6
(3),
p. 100131.
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BACKGROUND: European Society for Medical Oncology Women for Oncology (ESMO W4O) research has previously shown under-representation of female oncologists in leadership roles. As early reports suggested disproportionate effects of the COVID-19 pandemic on women, the ESMO W4O Committee initiated a study on the impact of the pandemic on the lives of female and male oncologists. METHODS: A questionnaire was sent to ESMO members and put on the ESMO website between 8 June 2020 and 2 July 2020. Questions focused on the working (hospital tasks, laboratory tasks, science) and home (household management, childcare, parent care, personal care) lives of oncologists during and after COVID-19-related lockdowns. RESULTS: Of 649 respondents, 541 completed the questionnaire. Of these, 58% reported that COVID-19 had affected their professional career, 83% of whom said this was in a negative way (85% of women versus 76% of men). Approximately 86% reported that COVID-19 had changed their personal life and 82% their family life. Women were again significantly more affected than men: personal life (89% versus 78%; P = 0.001); family life (84% versus 77%; P = 0.037). During lockdowns, women reported increased time spent on hospital and laboratory tasks compared with men (53% versus 46% and 33% versus 26%, respectively) and a significantly higher proportion of women than men spent less time on science (39% versus 25%) and personal care (58% versus 39%). After confinement, this trend remained for science (42% versus 23%) and personal care (55% versus 36%). CONCLUSIONS: The COVID-19 pandemic has adversely affected the professional and home lives of oncologists, especially women. Reduced research time for female oncologists may have long-lasting career consequences, especially for those at key stages in their career. The gender gap for promotion to leadership positions may widen further as a result of the pandemic..
Zhao, Y.
Fu, X.
Lopez, J.I.
Rowan, A.
Au, L.
Fendler, A.
Hazell, S.
Xu, H.
Horswell, S.
Shepherd, S.T.
Spain, L.
Byrne, F.
Stamp, G.
O'Brien, T.
Nicol, D.
Augustine, M.
Chandra, A.
Rudman, S.
Toncheva, A.
Pickering, L.
Sahai, E.
Larkin, J.
Bates, P.A.
Swanton, C.
Turajlic, S.
TRACERx Renal Consortium,
Litchfield, K.
(2021). Selection of metastasis competent subclones in the tumour interior. Nat ecol evol,
Vol.5
(7),
pp. 1033-1045.
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The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution..
Alexander, J.L.
Ibraheim, H.
Sheth, B.
Little, J.
Khan, M.S.
Richards, C.
Hunter, N.
Chauhan, D.
Ratnakumaran, R.
McHugh, K.
Pinato, D.J.
Nathan, P.
Choy, J.
Crusz, S.M.
Furness, A.
Turajlic, S.
Pickering, L.
Larkin, J.
Teare, J.P.
Papa, S.
Speight, A.
Sharma, A.
Powell, N.
(2021). Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab. J immunother cancer,
Vol.9
(7).
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INTRODUCTION: Immune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce. METHODS: We conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria. RESULTS: 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013). CONCLUSION: This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy..
Au, L.
Fendler, A.
Shepherd, S.T.
Rzeniewicz, K.
Cerrone, M.
Byrne, F.
Carlyle, E.
Edmonds, K.
Del Rosario, L.
Shon, J.
Haynes, W.A.
Ward, B.
Shum, B.
Gordon, W.
Gerard, C.L.
Xie, W.
Joharatnam-Hogan, N.
Young, K.
Pickering, L.
Furness, A.J.
Larkin, J.
Harvey, R.
Kassiotis, G.
Gandhi, S.
Crick COVID-19 Consortium,
Swanton, C.
Fribbens, C.
Wilkinson, K.A.
Wilkinson, R.J.
Lau, D.K.
Banerjee, S.
Starling, N.
Chau, I.
CAPTURE Consortium,
Turajlic, S.
(2021). Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2. Nat med,
Vol.27
(8),
pp. 1362-1366.
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full text
Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population..
Au, L.
Hatipoglu, E.
Robert de Massy, M.
Litchfield, K.
Beattie, G.
Rowan, A.
Schnidrig, D.
Thompson, R.
Byrne, F.
Horswell, S.
Fotiadis, N.
Hazell, S.
Nicol, D.
Shepherd, S.T.
Fendler, A.
Mason, R.
Del Rosario, L.
Edmonds, K.
Lingard, K.
Sarker, S.
Mangwende, M.
Carlyle, E.
Attig, J.
Joshi, K.
Uddin, I.
Becker, P.D.
Sunderland, M.W.
Akarca, A.
Puccio, I.
Yang, W.W.
Lund, T.
Dhillon, K.
Vasquez, M.D.
Ghorani, E.
Xu, H.
Spencer, C.
López, J.I.
Green, A.
Mahadeva, U.
Borg, E.
Mitchison, M.
Moore, D.A.
Proctor, I.
Falzon, M.
Pickering, L.
Furness, A.J.
Reading, J.L.
Salgado, R.
Marafioti, T.
Jamal-Hanjani, M.
PEACE Consortium,
Kassiotis, G.
Chain, B.
Larkin, J.
Swanton, C.
Quezada, S.A.
Turajlic, S.
TRACERx Renal Consortium,
(2021). Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma. Cancer cell,
Vol.39
(11),
pp. 1497-1518.e11.
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full text
ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action..
Fendler, A.
Shepherd, S.T.
Au, L.
Wilkinson, K.A.
Wu, M.
Byrne, F.
Cerrone, M.
Schmitt, A.M.
Joharatnam-Hogan, N.
Shum, B.
Tippu, Z.
Rzeniewicz, K.
Boos, L.A.
Harvey, R.
Carlyle, E.
Edmonds, K.
Del Rosario, L.
Sarker, S.
Lingard, K.
Mangwende, M.
Holt, L.
Ahmod, H.
Korteweg, J.
Foley, T.
Bazin, J.
Gordon, W.
Barber, T.
Emslie-Henry, A.
Xie, W.
Gerard, C.L.
Deng, D.
Wall, E.C.
Agua-Doce, A.
Namjou, S.
Caidan, S.
Gavrielides, M.
MacRae, J.I.
Kelly, G.
Peat, K.
Kelly, D.
Murra, A.
Kelly, K.
O'Flaherty, M.
Dowdie, L.
Ash, N.
Gronthoud, F.
Shea, R.L.
Gardner, G.
Murray, D.
Kinnaird, F.
Cui, W.
Pascual, J.
Rodney, S.
Mencel, J.
Curtis, O.
Stephenson, C.
Robinson, A.
Oza, B.
Farag, S.
Leslie, I.
Rogiers, A.
Iyengar, S.
Ethell, M.
Messiou, C.
Cunningham, D.
Chau, I.
Starling, N.
Turner, N.
Welsh, L.
van As, N.
Jones, R.L.
Droney, J.
Banerjee, S.
Tatham, K.C.
O'Brien, M.
Harrington, K.
Bhide, S.
Okines, A.
Reid, A.
Young, K.
Furness, A.J.
Pickering, L.
Swanton, C.
Crick COVID-19 Consortium,
Gandhi, S.
Gamblin, S.
Bauer, D.L.
Kassiotis, G.
Kumar, S.
Yousaf, N.
Jhanji, S.
Nicholson, E.
Howell, M.
Walker, S.
Wilkinson, R.J.
Larkin, J.
Turajlic, S.
CAPTURE Consortium,
(2021). Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study. Nat cancer,
Vol.2
(12),
pp. 1305-1320.
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full text
Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) ( NCT03226886 ) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic..
Berghoff, A.S.
Sessa, C.
Yang, J.C.
Tsourti, Z.
Tsang, J.
Tabernero, J.
Peters, S.
Linardou, H.
Letsch, A.
Haanen, J.
Garralda, E.
Garassino, M.C.
Furness, A.J.
Felip, E.
Dimopoulou, G.
Dafni, U.
Choo, S.P.
Banerjee, S.
Bajpai, J.
Adjei, A.A.
Garrido, P.
(2021). Female leadership in oncology-has progress stalled? Data from the ESMO W4O authorship and monitoring studies. Esmo open,
Vol.6
(6),
p. 100281.
show abstract
full text
BACKGROUND: Exploratory research showed that female oncologists are frequently under-represented in leadership roles. European Society for Medical Oncology (ESMO) Women for Oncology (W4O) therefore implemented gender equality programs in career development and established international studies on female representation at all stages of the oncology career pathway. METHODS: For 2017-2019, data were collected on (i) first and last authorship of publications in five major oncology journals and (ii) representation of women in leadership positions in oncology-as invited speakers at National/International congresses, board members or presidents of National/International societies and ESMO members. The 2015/2016 data from the first published W4O Study were incorporated for comparisons. RESULTS: Across 2017-2019, female oncologists were significantly more likely to be first than last authors (P < 0.001). The proportion of female first authors was similar across years: 38.0% in 2017, 37.1% in 2018, 41.0% in 2019 (P = 0.063). The proportion of female last authors decreased from 30.4% in 2017 to 24.2% in 2018 (P = 0.0018) and increased to 28.5% in 2019 (P = 0.018). Across 2015-2019, invited speakers at International/National oncology congresses were significantly less likely to be female than male (P < 0.001; 29.7% in 2015 to 36.8% in 2019). Across 2016-2019, board members of International/National oncology societies were significantly less likely to be female than male (P < 0.001; 26.8% in 2016 to 35.8% in 2019). There were statistically significant increasing trends in female speakers and board members across the study periods (P < 0.001 for both). Societies with a female president had a higher proportion of female board members across these periods (P = 0.026). CONCLUSIONS: Reported progress towards gender equality in career development in oncology is real but slow. Women in leadership positions are essential for encouraging young women to aspire to and work towards similar or greater success. Therefore, continued monitoring is needed to inform ESMO W4O initiatives to promote gender balance at all stages of the career pathway..
Fendler, A.
Au, L.
Shepherd, S.T.
Byrne, F.
Cerrone, M.
Boos, L.A.
Rzeniewicz, K.
Gordon, W.
Shum, B.
Gerard, C.L.
Ward, B.
Xie, W.
Schmitt, A.M.
Joharatnam-Hogan, N.
Cornish, G.H.
Pule, M.
Mekkaoui, L.
Ng, K.W.
Carlyle, E.
Edmonds, K.
Rosario, L.D.
Sarker, S.
Lingard, K.
Mangwende, M.
Holt, L.
Ahmod, H.
Stone, R.
Gomes, C.
Flynn, H.R.
Agua-Doce, A.
Hobson, P.
Caidan, S.
Howell, M.
Wu, M.
Goldstone, R.
Crawford, M.
Cubitt, L.
Patel, H.
Gavrielides, M.
Nye, E.
Snijders, A.P.
MacRae, J.I.
Nicod, J.
Gronthoud, F.
Shea, R.L.
Messiou, C.
Cunningham, D.
Chau, I.
Starling, N.
Turner, N.
Welsh, L.
van As, N.
Jones, R.L.
Droney, J.
Banerjee, S.
Tatham, K.C.
Jhanji, S.
O'Brien, M.
Curtis, O.
Harrington, K.
Bhide, S.
Bazin, J.
Robinson, A.
Stephenson, C.
Slattery, T.
Khan, Y.
Tippu, Z.
Leslie, I.
Gennatas, S.
Okines, A.
Reid, A.
Young, K.
Furness, A.J.
Pickering, L.
Gandhi, S.
Gamblin, S.
Swanton, C.
Crick COVID-19 Consortium,
Nicholson, E.
Kumar, S.
Yousaf, N.
Wilkinson, K.A.
Swerdlow, A.
Harvey, R.
Kassiotis, G.
Larkin, J.
Wilkinson, R.J.
Turajlic, S.
CAPTURE consortium,
(2021). Functional antibody and T cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study. Nat cancer,
Vol.2
(12),
pp. 1321-1337.
show abstract
full text
Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer..
Alrasheed, N.
Lee, L.
Ghorani, E.
Henry, J.Y.
Conde, L.
Chin, M.
Galas-Filipowicz, D.
Furness, A.J.
Chavda, S.J.
Richards, H.
De-Silva, D.
Cohen, O.C.
Patel, D.
Brooks, A.
Rodriguez-Justo, M.
Pule, M.
Herrero, J.
Quezada, S.A.
Yong, K.L.
(2020). Marrow-Infiltrating Regulatory T Cells Correlate with the Presence of Dysfunctional CD4+PD-1+ Cells and Inferior Survival in Patients with Newly Diagnosed Multiple Myeloma. Clin cancer res,
Vol.26
(13),
pp. 3443-3454.
show abstract
full text
PURPOSE: Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy. EXPERIMENTAL DESIGN: We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival. RESULTS: We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1-expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction. CONCLUSIONS: BM-infiltrating T-cell subsets, specifically Tregs and PD-1-expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies..
Dijksterhuis, W.P.
Stroes, C.I.
Tan, W.-.
Ithimakin, S.
Calles, A.
van Oijen, M.G.
Verhoeven, R.H.
Barriuso, J.
Oosting, S.F.
Ivankovic, D.K.
Furness, A.J.
Bozovic-Spasojevic, I.
Gomez-Roca, C.
van Laarhoven, H.W.
(2020). From presentation to paper: Gender disparities in oncological research. Int j cancer,
Vol.146
(11),
pp. 3011-3021.
show abstract
full text
Gender disparities in scientific publications have been identified in oncological research. Oral research presentations at major conferences enhance visibility of presenters. The share of women presenting at such podia is unknown. We aim to identify gender-based differences in contributions to presentations at two major oncological conferences. Abstracts presented at plenary sessions of the American Society of Clinical Oncology (ASCO) Annual Meetings and European Society for Medical Oncology (ESMO) Congresses were collected. Trend analyses were used to analyze female contribution over time. The association between presenter's sex, study outcome (positive/negative) and journals' impact factors (IFs) of subsequently published papers was assessed using Chi-square and Mann-Whitney U tests. Of 166 consecutive abstracts presented at ASCO in 2011-2018 (n = 34) and ESMO in 2008-2018 (n = 132), 21% had female presenters, all originating from Northern America (n = 17) or Europe (n = 18). The distribution of presenter's sex was similar over time (p = 0.70). Of 2,425 contributing authors to these presented abstracts, 28% were women. The proportion of female abstract authors increased over time (p < 0.05) and was higher in abstracts with female (34%) compared to male presenters (26%; p < 0.01). Presenter's sex was not associated with study outcome (p = 0.82). Median journals' IFs were lower in papers with a female first author (p < 0.05). In conclusion, there is a clear gender disparity in research presentations at two major oncological conferences, with 28% of authors and 21% of presenters of these studies being female. Lack of visibility of female presenters could impair acknowledgement for their research, opportunities in their academic career and even hamper heterogeneity in research..
Ghorani, E.
Reading, J.L.
Henry, J.Y.
Massy, M.R.
Rosenthal, R.
Turati, V.
Joshi, K.
Furness, A.J.
Ben Aissa, A.
Saini, S.K.
Ramskov, S.
Georgiou, A.
Sunderland, M.W.
Wong, Y.N.
Mucha, M.V.
Day, W.
Galvez-Cancino, F.
Becker, P.D.
Uddin, I.
Oakes, T.
Ismail, M.
Ronel, T.
Woolston, A.
Jamal-Hanjani, M.
Veeriah, S.
Birkbak, N.J.
Wilson, G.A.
Litchfield, K.
Conde, L.
Guerra-Assunção, J.A.
Blighe, K.
Biswas, D.
Salgado, R.
Lund, T.
Bakir, M.A.
Moore, D.A.
Hiley, C.T.
Loi, S.
Sun, Y.
Yuan, Y.
AbdulJabbar, K.
Turajilic, S.
Herrero, J.
Enver, T.
Hadrup, S.R.
Hackshaw, A.
Peggs, K.S.
McGranahan, N.
Chain, B.
TRACERx Consortium,
Swanton, C.
Quezada, S.A.
(2020). The T cell differentiation landscape is shaped by tumour mutations in lung cancer. Nat cancer,
Vol.1
(5),
pp. 546-561.
show abstract
full text
Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC..
Hagmayer, A.
Furness, A.I.
Reznick, D.N.
Dekker, M.L.
Pollux, B.J.
(2020). Predation risk shapes the degree of placentation in natural populations of live-bearing fish. Ecol lett,
Vol.23
(5),
pp. 831-840.
show abstract
The placenta is a complex life-history trait that is ubiquitous across the tree of life. Theory proposes that the placenta evolves in response to high performance-demanding conditions by shifting maternal investment from pre- to post-fertilisation, thereby reducing a female's reproductive burden during pregnancy. We test this hypothesis by studying populations of the fish species Poeciliopsis retropinna in Costa Rica. We found substantial variation in the degree of placentation among natural populations associated with predation risk: females from high predation populations had significantly higher degrees of placentation compared to low predation females, while number, size and quality of offspring at birth remained unaffected. Moreover, a higher degree of placentation correlated with a lower reproductive burden and hence likely an improved swimming performance during pregnancy. Our study advances an adaptive explanation for why the placenta evolves by arguing that an increased degree of placentation offers a selective advantage in high predation environments..
Pennycuick, A.
Teixeira, V.H.
AbdulJabbar, K.
Raza, S.E.
Lund, T.
Akarca, A.U.
Rosenthal, R.
Kalinke, L.
Chandrasekharan, D.P.
Pipinikas, C.P.
Lee-Six, H.
Hynds, R.E.
Gowers, K.H.
Henry, J.Y.
Millar, F.R.
Hagos, Y.B.
Denais, C.
Falzon, M.
Moore, D.A.
Antoniou, S.
Durrenberger, P.F.
Furness, A.J.
Carroll, B.
Marceaux, C.
Asselin-Labat, M.-.
Larson, W.
Betts, C.
Coussens, L.M.
Thakrar, R.M.
George, J.
Swanton, C.
Thirlwell, C.
Campbell, P.J.
Marafioti, T.
Yuan, Y.
Quezada, S.A.
McGranahan, N.
Janes, S.M.
(2020). Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer. Cancer discov,
Vol.10
(10),
pp. 1489-1499.
show abstract
full text
Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27-CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGNIFICANCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.See related commentary by Krysan et al., p. 1442.This article is highlighted in the In This Issue feature, p. 1426..
Comito, F.
Leslie, I.
Boos, L.
Furness, A.
Pickering, L.
Turajlic, S.
Larkin, J.
(2020). Oligoprogression After Checkpoint Inhibition in Metastatic Melanoma Treated With Locoregional Therapy: A Single-center Retrospective Analysis. J immunother,
Vol.43
(8),
pp. 250-255.
show abstract
Checkpoint inhibitors (CPIs) have demonstrated a heterogenous spectrum of response and disease progression that may not be fully captured by conventional response criteria, such as a limited degree of progression, known as oligoprogression, which could benefit from local treatment. We retrospectively analyzed data from all patients diagnosed with metastatic melanoma, who received CPI between January 2006 and March 2018 at Royal Marsden. We enrolled 36 patients who experienced progression in a maximum of 3 metastatic sites, after achieving disease control from therapy with CPI, and were radically treated with the locoregional approach. We carried out Kaplan-Meier analysis to obtain progression free-survival post-first oligoprogression (PFS-PO1), overall survival (OS) post-first oligoprogression, and OS estimates. The median time to oligoprogression from the start of CPI was 12 months. At a median follow-up of 34 months, the median PFS-PO1 was 32 months, with 50% of patients not progressed at the time of the data cutoff. The median OS-post-first oligoprogression was not reached. At a median follow-up of 52 months (from the first cycle of CPI), the median OS was not reached, with 75% of patients alive at the time of analysis. Univariate and multivariate analyses demonstrated that baseline American Joint Committee on Cancer stage IV M1a or M1b is associated with a longer PFS-PO1 compared with stage M1c or M1d. We observed that local therapy for oligoprogression after CPI can result in durable disease control, suggesting that locoregional treatment should be considered in patients being treated with immunotherapy. However, prospective evaluation, perhaps in randomized trials, is needed..
Hagmayer, A.
Furness, A.I.
Pollux, B.J.
(2020). Parasite infestation influences life history but not boldness behavior in placental live-bearing fish. Oecologia,
Vol.194
(4),
pp. 635-648.
show abstract
Parasites can negatively affect the reproductive success of hosts. Placental species may be particularly susceptible, because parasite-induced stress during pregnancy could potentially influence embryo development. Here, we examine the consequences of a trematode infestation (black spot disease, BSD) for fetal development and adult behavior in 19 natural populations of the placental live-bearing fish species Poeciliopsis retropinna (Poeciliidae) in Costa Rica. First, we observed substantial variation in parasite infestation among populations which correlated with a number of local environmental conditions (elevation, river width, depth, and flow velocity). Furthermore, we observed substantial variation in parasite infestation among females within populations associated with maternal age and size. We found that the infestation rate significantly influenced embryonic development, with more heavily parasitized females producing smaller and worse-conditioned offspring at birth, possibly, because a costly immune response during pregnancy limits, either directly or indirectly, nourishment to developing embryos. Finally, a behavioral experiment in the field showed that the infestation rate did not affect an individual's boldness. Our study indicates that in placental live-bearing fish parasite infestation leads to reduced embryo provisioning during pregnancy, resulting in a smaller offspring size and quality at birth potentially with negative implications for offspring fitness..
Draghi, A.
Chamberlain, C.A.
Furness, A.
Donia, M.
(2019). Acquired resistance to cancer immunotherapy. Semin immunopathol,
Vol.41
(1),
pp. 31-40.
show abstract
In recent times, advances in cancer immunotherapy have yielded impressive, durable clinical responses in patients with varied subtypes of cancer. However, a significant proportion of patients who initially demonstrate encouraging tumor regression develop resistance and progress over time. The identification of novel therapeutic approaches to overcome resistance may result in significantly improved clinical outcomes and remains an area of high scientific priority. This review aims to summarize the current knowledge regarding the role of both tumor-intrinsic and tumor-extrinsic factors in the development of resistance to cancer immunotherapy and to discuss current and possible future therapeutic strategies targeting these mechanisms..
Woolston, A.
Khan, K.
Spain, G.
Barber, L.J.
Griffiths, B.
Gonzalez-Exposito, R.
Hornsteiner, L.
Punta, M.
Patil, Y.
Newey, A.
Mansukhani, S.
Davies, M.N.
Furness, A.
Sclafani, F.
Peckitt, C.
Jiménez, M.
Kouvelakis, K.
Ranftl, R.
Begum, R.
Rana, I.
Thomas, J.
Bryant, A.
Quezada, S.
Wotherspoon, A.
Khan, N.
Fotiadis, N.
Marafioti, T.
Powles, T.
Lise, S.
Calvo, F.
Guettler, S.
von Loga, K.
Rao, S.
Watkins, D.
Starling, N.
Chau, I.
Sadanandam, A.
Cunningham, D.
Gerlinger, M.
(2019). Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer. Cancer cell,
Vol.36
(1),
pp. 35-50.e9.
show abstract
full text
Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy..
Joshi, K.
de Massy, M.R.
Ismail, M.
Reading, J.L.
Uddin, I.
Woolston, A.
Hatipoglu, E.
Oakes, T.
Rosenthal, R.
Peacock, T.
Ronel, T.
Noursadeghi, M.
Turati, V.
Furness, A.J.
Georgiou, A.
Wong, Y.N.
Ben Aissa, A.
Sunderland, M.W.
Jamal-Hanjani, M.
Veeriah, S.
Birkbak, N.J.
Wilson, G.A.
Hiley, C.T.
Ghorani, E.
Guerra-Assunção, J.A.
Herrero, J.
Enver, T.
Hadrup, S.R.
Hackshaw, A.
Peggs, K.S.
McGranahan, N.
Swanton, C.
TRACERx consortium,
Quezada, S.A.
Chain, B.
(2019). Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer. Nat med,
Vol.25
(10),
pp. 1549-1559.
show abstract
full text
Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy..
Furness, A.I.
Capellini, I.
(2019). The evolution of parental care diversity in amphibians. Nat commun,
Vol.10
(1),
p. 4709.
show abstract
Parental care is extremely diverse across species, ranging from simple behaviours to complex adaptations, varying in duration and in which sex cares. Surprisingly, we know little about how such diversity has evolved. Here, using phylogenetic comparative methods and data for over 1300 amphibian species, we show that egg attendance, arguably one of the simplest care behaviours, is gained and lost faster than any other care form, while complex adaptations, like brooding and viviparity, are lost at very low rates, if at all. Prolonged care from the egg to later developmental stages evolves from temporally limited care, but it is as easily lost as it is gained. Finally, biparental care is evolutionarily unstable regardless of whether the parents perform complementary or similar care duties. By considering the full spectrum of parental care adaptations, our study reveals a more complex and nuanced picture of how care evolves, is maintained, or is lost..
Furness, A.I.
Pollux, B.J.
Meredith, R.W.
Springer, M.S.
Reznick, D.N.
(2019). How conflict shapes evolution in poeciliid fishes. Nat commun,
Vol.10
(1),
p. 3335.
show abstract
In live-bearing animal lineages, the evolution of the placenta is predicted to create an arena for genomic conflict during pregnancy, drive patterns of male sexual selection, and increase the rate of speciation. Here we test these predictions of the viviparity driven conflict hypothesis (VDCH) in live-bearing poecilid fishes, a group showing multiple independent origins of placentation and extreme variation in male sexually selected traits. As predicted, male sexually selected traits are only gained in lineages that lack placentas; while there is little or no influence of male traits on the evolution of placentas. Both results are consistent with the mode of female provisioning governing the evolution of male attributes. Moreover, it is the presence of male sexually selected traits (pre-copulatory), rather than placentation (post-copulatory), that are associated with higher rates of speciation. These results highlight a causal interaction between female reproductive mode, male sexual selection and the rate of speciation, suggesting a role for conflict in shaping diverse aspects of organismal biology..
Samson, A.
Scott, K.J.
Taggart, D.
West, E.J.
Wilson, E.
Nuovo, G.J.
Thomson, S.
Corns, R.
Mathew, R.K.
Fuller, M.J.
Kottke, T.J.
Thompson, J.M.
Ilett, E.J.
Cockle, J.V.
van Hille, P.
Sivakumar, G.
Polson, E.S.
Turnbull, S.J.
Appleton, E.S.
Migneco, G.
Rose, A.S.
Coffey, M.C.
Beirne, D.A.
Collinson, F.J.
Ralph, C.
Alan Anthoney, D.
Twelves, C.J.
Furness, A.J.
Quezada, S.A.
Wurdak, H.
Errington-Mais, F.
Pandha, H.
Harrington, K.J.
Selby, P.J.
Vile, R.G.
Griffin, S.D.
Stead, L.F.
Short, S.C.
Melcher, A.A.
(2018). Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci transl med,
Vol.10
(422).
show abstract
full text
Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human Orthoreovirus (referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain..
Wong, Y.N.
Joshi, K.
Khetrapal, P.
Ismail, M.
Reading, J.L.
Sunderland, M.W.
Georgiou, A.
Furness, A.J.
Ben Aissa, A.
Ghorani, E.
Oakes, T.
Uddin, I.
Tan, W.S.
Feber, A.
McGovern, U.
Swanton, C.
Freeman, A.
Marafioti, T.
Briggs, T.P.
Kelly, J.D.
Powles, T.
Peggs, K.S.
Chain, B.M.
Linch, M.D.
Quezada, S.A.
(2018). Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment. J exp med,
Vol.215
(11),
pp. 2748-2759.
show abstract
full text
Despite the advances in cancer immunotherapy, only a fraction of patients with bladder cancer exhibit responses to checkpoint blockade, highlighting a need to better understand drug resistance and identify rational immunotherapy combinations. However, accessibility to the tumor prior and during therapy is a major limitation in understanding the immune tumor microenvironment (TME). Herein, we identified urine-derived lymphocytes (UDLs) as a readily accessible source of T cells in 32 patients with muscle invasive bladder cancer (MIBC). We observed that effector CD8+ and CD4+ cells and regulatory T cells within the urine accurately map the immune checkpoint landscape and T cell receptor repertoire of the TME. Finally, an increased UDL count, specifically high expression of PD-1 (PD-1hi) on CD8+ at the time of cystectomy, was associated with a shorter recurrence-free survival. UDL analysis represents a dynamic liquid biopsy that is representative of the bladder immune TME that may be used to identify actionable immuno-oncology (IO) targets with potential prognostic value in MIBC..
Arce Vargas, F.
Furness, A.J.
Litchfield, K.
Joshi, K.
Rosenthal, R.
Ghorani, E.
Solomon, I.
Lesko, M.H.
Ruef, N.
Roddie, C.
Henry, J.Y.
Spain, L.
Ben Aissa, A.
Georgiou, A.
Wong, Y.N.
Smith, M.
Strauss, D.
Hayes, A.
Nicol, D.
O'Brien, T.
Mårtensson, L.
Ljungars, A.
Teige, I.
Frendéus, B.
TRACERx Melanoma,
TRACERx Renal,
TRACERx Lung consortia,
Pule, M.
Marafioti, T.
Gore, M.
Larkin, J.
Turajlic, S.
Swanton, C.
Peggs, K.S.
Quezada, S.A.
(2018). Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Cancer cell,
Vol.33
(4),
pp. 649-663.e4.
show abstract
full text
With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches..
Hagmayer, A.
Furness, A.I.
Reznick, D.N.
Pollux, B.J.
(2018). Maternal size and body condition predict the amount of post-fertilization maternal provisioning in matrotrophic fish. Ecol evol,
Vol.8
(24),
pp. 12386-12396.
show abstract
Maternal effects often provide a mechanism for adaptive transgenerational phenotypic plasticity. The maternal phenotype can profoundly influence the potential for such environmentally induced adjustments of the offspring phenotype, causing correlations between offspring and maternal traits. Here, we study potential effects of the maternal phenotype on offspring provisioning prior to and during gestation in the matrotrophic live-bearing fish species Poeciliopsis retropinna. Specifically, we examine how maternal traits such as body fat, lean mass, and length relate to pre- (i.e., allocation to the egg prior to fertilization) and post-fertilization (i.e., allocation to the embryo during pregnancy) maternal provisioning and how this ultimately affects offspring size and body composition at birth. We show that pre- and post-fertilization maternal provisioning is associated with maternal length and body fat, but not with maternal lean mass. Maternal length is proportionally associated with egg mass at fertilization and offspring mass at birth, notably without changing the ratio of pre- to post-fertilization maternal provisioning. This ratio, referred to as the matrotrophy index (MI), is often used to quantify the level of matrotrophy. By contrast, the proportion of maternal body fat is positively associated with post-fertilization, but not pre-fertilization, maternal provisioning and consequently is strongly positively correlated with the MI. We furthermore found that the composition of embryos changes throughout pregnancy. Females invest first in embryo lean mass, and then allocate fat reserves to embryos very late in pregnancy. We argue that this delay in fat allocation may be adaptive, because it delays an unnecessary high reproductive burden to the mother during earlier stages of pregnancy, potentially leading to a more slender body shape and improved locomotor performance. In conclusion, our study suggests that (a) offspring size at birth is a plastic trait that is predicted by both maternal length and body fat, and (b) the MI is a plastic trait that is predicted solely by the proportion of maternal body fat. It herewith provides new insights into the potential maternal causes and consequences of embryo provisioning during pregnancy in matrotrophic live-bearing species..
Chakravarthy, A.
Furness, A.
Joshi, K.
Ghorani, E.
Ford, K.
Ward, M.J.
King, E.V.
Lechner, M.
Marafioti, T.
Quezada, S.A.
Thomas, G.J.
Feber, A.
Fenton, T.R.
(2018). Pan-cancer deconvolution of tumour composition using DNA methylation. Nat commun,
Vol.9
(1),
p. 3220.
show abstract
full text
The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: 'immune hot' and 'immune cold', which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to cytotoxic T-lymphocyte infiltration, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations, potentially explaining the heterogeneity of immunotherapy response and prognosis seen within this group. Finally, we define a catalogue of mediators of active antitumour immunity, deriving candidate biomarkers and potential targets for precision immunotherapy..
Furness, A.I.
Reznick, D.N.
Tatarenkov, A.
Avise, J.C.
(2018). The evolution of diapause in Rivulus (Laimosemion). Zoological journal of the linnean society,
Vol.184
(3),
pp. 773-790.
Linch, M.
Goh, G.
Hiley, C.
Shanmugabavan, Y.
McGranahan, N.
Rowan, A.
Wong, Y.N.
King, H.
Furness, A.
Freeman, A.
Linares, J.
Akarca, A.
Herrero, J.
Rosenthal, R.
Harder, N.
Schmidt, G.
Wilson, G.A.
Birkbak, N.J.
Mitter, R.
Dentro, S.
Cathcart, P.
Arya, M.
Johnston, E.
Scott, R.
Hung, M.
Emberton, M.
Attard, G.
Szallasi, Z.
Punwani, S.
Quezada, S.A.
Marafioti, T.
Gerlinger, M.
Ahmed, H.U.
Swanton, C.
(2017). Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters. Ann oncol,
Vol.28
(10),
pp. 2472-2480.
show abstract
full text
BACKGROUND: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. PATIENTS AND METHODS: Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy. Seventy-nine tumour regions from 25 patients with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification. RESULTS: We demonstrated extensive somatic nucleotide variation and somatic copy number alteration heterogeneity in high-risk PC. Overall, the mutational burden was low (0.93/Megabase), but two patients had hypermutation, with loss of mismatch repair (MMR) proteins, MSH2 and MSH6. Somatic copy number alteration burden was higher in patients with metastatic hormone-naive PC (mHNPC) than in those with high-risk localised PC (hrlPC), independent of Gleason grade. Mutations were rarely ubiquitous and mutational frequencies were similar for mHNPC and hrlPC patients. Enrichment of focal 3q26.2 and 3q21.3, regions containing putative metastasis drivers, was seen in mHNPC patients. We found evidence of parallel evolution with three separate clones containing activating mutations of β-catenin in a single patient. We demonstrated extensive intratumoural and intertumoural T-cell heterogeneity and high inflammatory infiltrate in the MMR-deficient (MMRD) patients and the patient with parallel evolution of β-catenin. Analysis of all patients with activating Wnt/β-catenin mutations demonstrated a low CD8+/FOXP3+ ratio, a potential surrogate marker of immune evasion. CONCLUSIONS: The PROGENY (PROstate cancer GENomic heterogeneitY) study provides a diagnostic platform suitable for studying tumour ITH. Genetic aberrations in clinically high-risk PC are associated with altered patterns of immune infiltrate in tumours. Activating mutations of Wnt/β-catenin signalling pathway or MMRD could be considered as potential biomarkers for immunomodulation therapies. CLINICAL TRIALS.GOV IDENTIFIER: NCT02022371..
Thompson, A.W.
Furness, A.I.
Stone, C.
Rade, C.M.
Ortí, G.
(2017). Microanatomical diversification of the zona pellucida in aplochelioid killifishes. J fish biol,
Vol.91
(1),
pp. 126-143.
show abstract
This study investigates zona pellucida (ZP) ultrastructure in fertilized eggs of annual killifishes (suborder Aplocheiloidei), a group of highly specialized fishes that are able to survive desiccation for several weeks to months before they hatch. Little is known about ZP or chorionic ultrastructure sustaining these life-history modes, so scanning electron microscopy (SEM) was used to describe this trait in a large number of aplocheiloids with a focus on the family Rivulidae and the genus Hypsolebias. New images of ZP ultrastructure for 52 aplocheiloid species are provided, more than doubling the number characterized thus far. The evolution of chorionic structure within this group is studied using these new data. Characters were coded into a morphological matrix and optimized onto a consensus phylogeny to assess phylogenetic signal and reconstruct ancestral character states. Although ZP characters seem highly homoplastic and exhibit a large amount of structural convergence among lineages, aplocheiloid killifishes have evolved a number of unique structures associated with the chorion. Some annual species seem to have lost long filaments because eggs are deposited in the soil instead of being adhered to aquatic plants..
Arce Vargas, F.
Furness, A.J.
Solomon, I.
Joshi, K.
Mekkaoui, L.
Lesko, M.H.
Miranda Rota, E.
Dahan, R.
Georgiou, A.
Sledzinska, A.
Ben Aissa, A.
Franz, D.
Werner Sunderland, M.
Wong, Y.N.
Henry, J.Y.
O'Brien, T.
Nicol, D.
Challacombe, B.
Beers, S.A.
Melanoma TRACERx Consortium,
Renal TRACERx Consortium,
Lung TRACERx Consortium,
Turajlic, S.
Gore, M.
Larkin, J.
Swanton, C.
Chester, K.A.
Pule, M.
Ravetch, J.V.
Marafioti, T.
Peggs, K.S.
Quezada, S.A.
(2017). Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors. Immunity,
Vol.46
(4),
pp. 577-586.
show abstract
full text
CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology..
Abbosh, C.
Birkbak, N.J.
Wilson, G.A.
Jamal-Hanjani, M.
Constantin, T.
Salari, R.
Le Quesne, J.
Moore, D.A.
Veeriah, S.
Rosenthal, R.
Marafioti, T.
Kirkizlar, E.
Watkins, T.B.
McGranahan, N.
Ward, S.
Martinson, L.
Riley, J.
Fraioli, F.
Al Bakir, M.
Grönroos, E.
Zambrana, F.
Endozo, R.
Bi, W.L.
Fennessy, F.M.
Sponer, N.
Johnson, D.
Laycock, J.
Shafi, S.
Czyzewska-Khan, J.
Rowan, A.
Chambers, T.
Matthews, N.
Turajlic, S.
Hiley, C.
Lee, S.M.
Forster, M.D.
Ahmad, T.
Falzon, M.
Borg, E.
Lawrence, D.
Hayward, M.
Kolvekar, S.
Panagiotopoulos, N.
Janes, S.M.
Thakrar, R.
Ahmed, A.
Blackhall, F.
Summers, Y.
Hafez, D.
Naik, A.
Ganguly, A.
Kareht, S.
Shah, R.
Joseph, L.
Marie Quinn, A.
Crosbie, P.A.
Naidu, B.
Middleton, G.
Langman, G.
Trotter, S.
Nicolson, M.
Remmen, H.
Kerr, K.
Chetty, M.
Gomersall, L.
Fennell, D.A.
Nakas, A.
Rathinam, S.
Anand, G.
Khan, S.
Russell, P.
Ezhil, V.
Ismail, B.
Irvin-Sellers, M.
Prakash, V.
Lester, J.F.
Kornaszewska, M.
Attanoos, R.
Adams, H.
Davies, H.
Oukrif, D.
Akarca, A.U.
Hartley, J.A.
Lowe, H.L.
Lock, S.
Iles, N.
Bell, H.
Ngai, Y.
Elgar, G.
Szallasi, Z.
Schwarz, R.F.
Herrero, J.
Stewart, A.
Quezada, S.A.
Peggs, K.S.
Van Loo, P.
Dive, C.
Lin, C.J.
Rabinowitz, M.
Aerts, H.J.
Hackshaw, A.
Shaw, J.A.
Zimmermann, B.G.
TRACERx consortium,
PEACE consortium,
Swanton, C.
(2017). Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature,
Vol.545
(7655),
pp. 446-451.
show abstract
The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies..
Reznick, D.N.
Furness, A.I.
Meredith, R.W.
Springer, M.S.
(2017). The origin and biogeographic diversification of fishes in the family Poeciliidae. Plos one,
Vol.12
(3),
p. e0172546.
show abstract
The fish subfamily Poeciliinae (sensu Parenti, 1981) is widely distributed across the Western Hemisphere and a dominant component of the fish communities of Central America. Poeciliids have figured prominently in previous studies on the roles of dispersal and vicariance in shaping current geographic distributions. Most recently, Hrbek et al. combined a DNA-based phylogeny of the family with geological models to provide a biogeographic perspective that emphasized the role of both vicariance and dispersal. Here we expand on that effort with a database enlarged in the quantity of sequence represented per species, in the number of species included, and in an enlarged and more balanced representation of the order Cyprinodontiformes. We combine a robust timetree based upon multiple fossil calibrations with enhanced biogeographic analyses that include ancestral area reconstructions to provide a detailed biogeographic history of this clade. Key features of our results are that the family originated in South America, but its major diversification dates to a later colonization of Central America. We also resolve additional colonizations among South, Central and North America and the Caribbean and consider how this reconstruction contributes to our understanding of the mechanisms of dispersal..
Patterson, B.M.
Lee, M.
Bastow, T.P.
Wilson, J.T.
Donn, M.J.
Furness, A.
Goodwin, B.
Manefield, M.
(2016). Concentration effects on biotic and abiotic processes in the removal of 1,1,2-trichloroethane and vinyl chloride using carbon-amended ZVI. Journal of contaminant hydrology,
Vol.188,
pp. 1-11.
Furness, A.J.
Quezada, S.A.
Peggs, K.S.
(2016). Neoantigen heterogeneity: a key driver of immune response and sensitivity to immune checkpoint blockade?. Immunotherapy,
Vol.8
(7),
pp. 763-766.
Furness, A.I.
Reznick, D.N.
Avise, J.C.
(2016). Ecological, evolutionary and human‐mediated determinants of poeciliid species richness on Caribbean islands. Journal of biogeography,
Vol.43
(7),
pp. 1349-1359.
show abstract
AbstractAimThe theory of island biogeography provides a predictive framework relating species richness to island size and distance from the mainland. However, the theory as originally formulated does not necessarily scale to large islands and continental landmasses that are capable of generating species through in situ speciation (rather than entirely by colonization), nor does it necessarily account for how human introduction of species alters traditional biogeographical patterns. Here, we examine the ecological (colonization and extinction), evolutionary (in situ speciation) and human‐mediated (deliberate introductions) determinants of species richness in a taxonomic group that has undergone a radiation on Caribbean islands: live‐bearing fishes of the family Poeciliidae.LocationThe Caribbean.MethodsWe created a database of both native and introduced poeciliid species occurrence on Caribbean islands through literature review, and estimated the number of colonizations versus speciation events on each island using a molecular phylogeny. Linear regression and other statistical tests were used to explore species–area and species–isolation relationships.ResultsSpecies richness on small islands results entirely from colonization and does not significantly increase with island area, whereas on larger islands species richness increases dramatically as a function of area due primarily to in situ speciation. Poeciliid fishes have been introduced widely, both as a by‐product of their popularity in the aquarium hobby and as a means of mosquito control. We show that such establishments have occurred disproportionately on islands depauperate in native species, and that introduced species richness is positively correlated with economic interconnectedness (shipping traffic) and human population size.Main conclusionsOn large Caribbean islands in situ speciation has elevated the number of poeciliid species beyond that predicted from ecological processes alone. Introduced species significantly alter biogeographical patterns..
Furness, A.I.
(2016). The evolution of an annual life cycle in killifish: adaptation to ephemeral aquatic environments through embryonic diapause. Biol rev camb philos soc,
Vol.91
(3),
pp. 796-812.
show abstract
An annual life cycle is characterized by growth, maturity, and reproduction condensed into a single, short season favourable to development, with production of embryos (seeds, cysts, or eggs) capable of surviving harsh conditions which juveniles or adults cannot tolerate. More typically associated with plants in desert environments, or temperate-zone insects exposed to freezing winters, the evolution of an annual life cycle in vertebrates is fairly novel. Killifish, small sexually dimorphic fishes in the Order Cyprinodontiformes, have adapted to seasonally ephemeral water bodies across much of Africa and South America through the independent evolution of an annual life history. These annual killifish produce hardy desiccation-resistant eggs that undergo diapause (developmental arrest) and remain buried in the soil for long periods when fish have perished due to the drying of their habitat. Killifish are found in aquatic habitats that span a continuum from permanent and stable to seasonal and variable, thus providing a useful system in which to piece together the evolutionary history of this life cycle using natural comparative variation. I first review adaptations for life in ephemeral aquatic environments in killifish, with particular emphasis on the evolution of embryonic diapause. I then bring together available evidence from a variety of approaches and provide a scenario for how this annual life cycle evolved. There are a number of features within Aplocheiloidei killifish including their inhabitation of marginal or edge aquatic habitat, their small size and rapid attainment of maturity, and egg properties that make them particularly well suited to the colonization of ephemeral waters..
Bentzen, A.K.
Marquard, A.M.
Lyngaa, R.
Saini, S.K.
Ramskov, S.
Donia, M.
Such, L.
Furness, A.J.
McGranahan, N.
Rosenthal, R.
Straten, P.T.
Szallasi, Z.
Svane, I.M.
Swanton, C.
Quezada, S.A.
Jakobsen, S.N.
Eklund, A.C.
Hadrup, S.R.
(2016). Large-scale detection of antigen-specific T cells using peptide-MHC-I multimers labeled with DNA barcodes. Nat biotechnol,
Vol.34
(10),
pp. 1037-1045.
show abstract
Identification of the peptides recognized by individual T cells is important for understanding and treating immune-related diseases. Current cytometry-based approaches are limited to the simultaneous screening of 10-100 distinct T-cell specificities in one sample. Here we use peptide-major histocompatibility complex (MHC) multimers labeled with individual DNA barcodes to screen >1,000 peptide specificities in a single sample, and detect low-frequency CD8 T cells specific for virus- or cancer-restricted antigens. When analyzing T-cell recognition of shared melanoma antigens before and after adoptive cell therapy in melanoma patients, we observe a greater number of melanoma-specific T-cell populations compared with cytometry-based approaches. Furthermore, we detect neoepitope-specific T cells in tumor-infiltrating lymphocytes and peripheral blood from patients with non-small cell lung cancer. Barcode-labeled pMHC multimers enable the combination of functional T-cell analysis with large-scale epitope recognition profiling for the characterization of T-cell recognition in various diseases, including in small clinical samples..
McGranahan, N.
Furness, A.J.
Rosenthal, R.
Ramskov, S.
Lyngaa, R.
Saini, S.K.
Jamal-Hanjani, M.
Wilson, G.A.
Birkbak, N.J.
Hiley, C.T.
Watkins, T.B.
Shafi, S.
Murugaesu, N.
Mitter, R.
Akarca, A.U.
Linares, J.
Marafioti, T.
Henry, J.Y.
Van Allen, E.M.
Miao, D.
Schilling, B.
Schadendorf, D.
Garraway, L.A.
Makarov, V.
Rizvi, N.A.
Snyder, A.
Hellmann, M.D.
Merghoub, T.
Wolchok, J.D.
Shukla, S.A.
Wu, C.J.
Peggs, K.S.
Chan, T.A.
Hadrup, S.R.
Quezada, S.A.
Swanton, C.
(2016). Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science,
Vol.351
(6280),
pp. 1463-1469.
show abstract
As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+)tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens..
Wilkins, A.
Furness, A.
Corbett, R.W.
Bloomfield, A.
Porta, N.
Morris, S.
Ali, Z.
Larkin, J.
Harrington, K.
(2015). The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma. Br j cancer,
Vol.113
(9),
pp. 1275-1281.
show abstract
full text
BACKGROUND: The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations. METHODS: Performance of the msGPA was assessed in Cohort I (1997-2008, n=231) and Cohort II (2008-2013, n=162) using Kaplan-Meier methods and Harrell's c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance. RESULTS: The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models. CONCLUSIONS: An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care..
Alotaibi, M.D.
Patterson, B.M.
McKinley, A.J.
Reeder, A.Y.
Furness, A.J.
Donn, M.J.
(2015). Fate of benzotriazole and 5-methylbenzotriazole in recycled water recharged into an anaerobic aquifer: Column studies. Water research,
Vol.70,
pp. 184-195.
Martin-Liberal, J.
Furness, A.J.
Joshi, K.
Peggs, K.S.
Quezada, S.A.
Larkin, J.
(2015). Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer immunol immunother,
Vol.64
(6),
pp. 765-767.
show abstract
The anti programmed cell death-1 (PD-1) antibodies pembrolizumab and nivolumab have been recently licensed by the Food and Drug Administration for the treatment of advanced melanoma. Immune checkpoint inhibitors such as these can induce endocrine adverse events but autoimmune diabetes has not been described to date. However, there is a strong preclinical rationale that supports this autoimmune toxicity. We describe for the first time the case of an adult patient who developed autoimmune diabetes likely as a consequence of PD-1 inhibition with pembrolizumab. The presence of high serum titres of anti-glutamic acid decarboxylase antibodies together with a suggestive clinical presentation, age of the patient and preclinical data strongly support an autoimmune aetiology of the diabetes. Moreover, the patient was found to have a well-known high-risk human leucocyte antigen type for the development of type 1 diabetes in children, so the PD-1 inhibition is very likely to have triggered the autoimmune phenomenon. Our case suggests that insulin-dependent diabetes might be a rare but important anti-PD-1 immune-related adverse event..
Furness, A.I.
Lee, K.
Reznick, D.N.
(2015). Adaptation in a variable environment: Phenotypic plasticity and bet-hedging during egg diapause and hatching in an annual killifish. Evolution,
Vol.69
(6),
pp. 1461-1475.
show abstract
Two ways in which organisms adapt to variable environments are phenotypic plasticity and bet-hedging. Theory suggests that bet-hedging is expected to evolve in unpredictable environments for which reliable cues indicative of future conditions (or season length) are lacking. Alternatively, if reliable cues exist indicating future conditions, organisms will be under selection to produce the most appropriate phenotype -that is, adaptive phenotypic plasticity. Here, we experimentally test which of these modes of adaptation are at play in killifish that have evolved an annual life cycle. These fish persist in ephemeral pools that completely dry each season through the production of eggs that can remain in developmental arrest, or diapause, buried in the soil, until the following rainy season. Consistent with diversified bet-hedging (a risk spreading strategy), we demonstrate that the eggs of the annual killifish Nothobranchius furzeri exhibit variation at multiple levels-whether or not different stages of diapause are entered, for how long diapause is entered, and the timing of hatching-and this variation persists after controlling for both genetic and environmental sources of variation. However, we show that phenotypic plasticity is also present in that the proportion of eggs that enter diapause is influenced by environmental factors (temperature and light level) that vary seasonally. In nature there is typically a large parameter zone where environmental cues are somewhat correlated with seasonality, but not perfectly so, such that it may be advantageous to have a combination of both bet-hedging and plasticity..
Furness, A.I.
Reznick, D.N.
Springer, M.S.
Meredith, R.W.
(2015). Convergent evolution of alternative developmental trajectories associated with diapause in African and South American killifish. Proc biol sci,
Vol.282
(1802).
show abstract
Annual killifish adapted to life in seasonally ephemeral water-bodies exhibit desiccation resistant eggs that can undergo diapause, a period of developmental arrest, enabling them to traverse the otherwise inhospitable dry season. Environmental cues that potentially indicate the season can govern whether eggs enter a stage of diapause mid-way through development or skip this diapause and instead undergo direct development. We report, based on construction of a supermatrix phylogenetic tree of the order Cyprinodontiformes and a battery of comparative analyses, that the ability to produce diapause eggs evolved independently at least six times within African and South American killifish. We then show in species representative of these lineages that embryos entering diapause display significant reduction in development of the cranial region and circulatory system relative to direct-developing embryos. This divergence along alternative developmental pathways begins mid-way through development, well before diapause is entered, during a period of purported maximum developmental constraint (the phylotypic period). Finally, we show that entering diapause is accompanied by a dramatic reduction in metabolic rate and concomitant increase in long-term embryo survival. Morphological divergence during the phylotypic period thus allows embryos undergoing diapause to conserve energy by shunting resources away from energetically costly organs thereby increasing survival chances in an environment that necessitates remaining dormant, buried in the soil and surrounded by an eggshell for much of the year. Our results indicate that adaptation to seasonal aquatic environments in annual killifish imposes strong selection during the embryo stage leading to marked diversification during this otherwise conserved period of vertebrate development..
Furness, A.I.
Tatarenkov, A.
Avise, J.C.
(2015). A Genetic Test for Whether Pairs of Hermaphrodites Can Cross-Fertilize in a Selfing Killifish. J hered,
Vol.106
(6),
pp. 749-752.
show abstract
Kryptolebias marmoratus, a small killifish that lives in mangrove habitat from southern Florida to Brazil, is one of the planet's only known self-fertilizing hermaphroditic vertebrates. Generation after generation, hermaphroditic individuals simultaneously produce sperm and eggs and internally self-fertilize to produce what are, in effect, highly inbred clones of themselves. Although populations are composed primarily of hermaphrodites, they also contain some true males. The frequency of males in a population varies geographically, from <2% in Florida to as high as 25% in Belize. Males are known to mate occasionally with hermaphrodites, thereby releasing genetic variation that has profound consequences for population genetic structure. However, it is unknown whether hermaphrodites can or do sporadically mate with each other also. Here, we test whether hermaphroditic individuals of the killifish Kryptolebias marmoratus are capable of crossing with one another, in addition to their much more common habits of self-fertilization and occasional outcrossing with pure males. We employ an experimental design in which replicate hermaphrodite pairs were housed together and allowed to reproduce naturally. Among 173 embryos screened at diagnostic microsatellite loci, all were found to result from selfing (i.e., no embryos were the product of a hermaphrodite cross). We thus conclude that hermaphrodite pairs are unlikely to cross, or do so exceedingly rarely..
Furness, A.I.
Reznick, D.N.
(2014). The comparative ecology of a killifish (Rivulus hartii) across aquatic communities differing in predation intensity. Evolutionary ecology research,
Vol.16
(3),
pp. 249-17.
Kelderman, S.
Heemskerk, B.
van Tinteren, H.
van den Brom, R.R.
Hospers, G.A.
van den Eertwegh, A.J.
Kapiteijn, E.W.
de Groot, J.W.
Soetekouw, P.
Jansen, R.L.
Fiets, E.
Furness, A.J.
Renn, A.
Krzystanek, M.
Szallasi, Z.
Lorigan, P.
Gore, M.E.
Schumacher, T.N.
Haanen, J.B.
Larkin, J.M.
Blank, C.U.
(2014). Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer immunol immunother,
Vol.63
(5),
pp. 449-458.
show abstract
INTRODUCTION: Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit. METHODS: Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. RESULTS: A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK. CONCLUSION: In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy..
Furness, A.J.
Vargas, F.A.
Peggs, K.S.
Quezada, S.A.
(2014). Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies. Trends immunol,
Vol.35
(7),
pp. 290-298.
show abstract
Immunomodulatory antibodies influence the direction and magnitude of immune responses against cancer. Significant efficacy has been demonstrated across multiple solid tumour types within clinical trials. Recent preclinical studies indicate that successful outcome relies upon mechanistic activity extending beyond simple receptor stimulation or blockade. In addition to blocking co-inhibitory signals in secondary lymphoid organs, cytotoxic T-lymphocyte antigen (CTLA)-4 antibodies mediate depletion of tumour-infiltrating regulatory T cells by antibody-dependent cellular cytotoxicity (ADCC). This mechanism appears to be common to other immunomodulatory antibodies including those targeting OX40 and glucocorticoid-induced TNFR-related protein (GITR). If verified in the human setting, these findings have significant implications for antibody design, biomarker discovery, and the development of synergistic combinatorial therapies..
Bekele, E.
Patterson, B.
Toze, S.
Furness, A.
Higginson, S.
Shackleton, M.
(2014). Aquifer residence times for recycled water estimated using chemical tracers and the propagation of temperature signals at a managed aquifer recharge site in Australia. Hydrogeology journal,
Vol.22
(6),
pp. 1383-1401.
Johnston, C.D.
Davis, G.B.
Bastow, T.P.
Annable, M.D.
Trefry, M.G.
Furness, A.
Geste, Y.
Woodbury, R.J.
Rao, P.S.
Rhodes, S.
(2013). The use of mass depletion–mass flux reduction relationships during pumping to determine source zone mass of a reactive brominated-solvent DNAPL. Journal of contaminant hydrology,
Vol.144
(1),
pp. 122-137.
Patterson, B.M.
Aravena, R.
Davis, G.B.
Furness, A.J.
Bastow, T.P.
Bouchard, D.
(2013). Multiple lines of evidence to demonstrate vinyl chloride aerobic biodegradation in the vadose zone, and factors controlling rates. Journal of contaminant hydrology,
Vol.153,
pp. 69-77.
Gerlinger, M.
Quezada, S.A.
Peggs, K.S.
Furness, A.J.
Fisher, R.
Marafioti, T.
Shende, V.H.
McGranahan, N.
Rowan, A.J.
Hazell, S.
Hamm, D.
Robins, H.S.
Pickering, L.
Gore, M.
Nicol, D.L.
Larkin, J.
Swanton, C.
(2013). Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas. J pathol,
Vol.231
(4),
pp. 424-432.
show abstract
The recognition of cancer cells by T cells can impact upon prognosis and be exploited for immunotherapeutic approaches. This recognition depends on the specific interaction between antigens displayed on the surface of cancer cells and the T cell receptor (TCR), which is generated by somatic rearrangements of TCR α- and β-chains (TCRb). Our aim was to assess whether ultra-deep sequencing of the rearranged TCRb in DNA extracted from unfractionated clear cell renal cell carcinoma (ccRCC) samples can provide insights into the clonality and heterogeneity of intratumoural T cells in ccRCCs, a tumour type that can display extensive genetic intratumour heterogeneity (ITH). For this purpose, DNA was extracted from two to four tumour regions from each of four primary ccRCCs and was analysed by ultra-deep TCR sequencing. In parallel, tumour infiltration by CD4, CD8 and Foxp3 regulatory T cells was evaluated by immunohistochemistry and correlated with TCR-sequencing data. A polyclonal T cell repertoire with 367-16 289 (median 2394) unique TCRb sequences was identified per tumour region. The frequencies of the 100 most abundant T cell clones/tumour were poorly correlated between most regions (Pearson correlation coefficient, -0.218 to 0.465). 3-93% of these T cell clones were not detectable across all regions. Thus, the clonal composition of T cell populations can be heterogeneous across different regions of the same ccRCC. T cell ITH was higher in tumours pretreated with an mTOR inhibitor, which could suggest that therapy can influence adaptive tumour immunity. These data show that ultra-deep TCR-sequencing technology can be applied directly to DNA extracted from unfractionated tumour samples, allowing novel insights into the clonality of T cell populations in cancers. These were polyclonal and displayed ITH in ccRCC. TCRb sequencing may shed light on mechanisms of cancer immunity and the efficacy of immunotherapy approaches..
Patterson, B.M.
Furness, A.J.
Bastow, T.P.
(2013). Soil gas carbon dioxide probe: laboratory testing and field evaluation. Environmental science: processes & impacts,
Vol.15
(5),
pp. 1062-1062.
Patterson, B.M.
Pitoi, M.M.
Furness, A.J.
Bastow, T.P.
McKinley, A.J.
(2012). Fate of N-Nitrosodimethylamine in recycled water after recharge into anaerobic aquifer. Water research,
Vol.46
(4),
pp. 1260-1272.
Furness, A.I.
Walsh, M.R.
Reznick, D.N.
(2012). Convergence of life-history phenotypes in a Trinidadian killifish (Rivulus hartii). Evolution,
Vol.66
(4),
pp. 1240-1254.
show abstract
Convergent evolution is characterized by the independent evolution of similar phenotypes within similar selective environments. Previous work on Trinidadian killifish, Rivulus hartii, demonstrated repeatable life-history differences across communities that differ in predation intensity. These studies were performed in rivers located on the south slope of Trinidad's Northern Range Mountains. There exists a parallel series of rivers on the north slope of these mountains. As on the south slope, Rivulus is found across a gradient of fish predation. However, the predatory fish species in north-slope rivers are derived from marine families, whereas south-slope rivers contain a predatory fish fauna characteristic of the South American mainland. If predator-induced mortality and the associated indirect effects are the causal factors selecting for life-history patterns in Rivulus, and these are similar in north- and south-slope rivers, then the specific predatory species should be interchangeable and we would expect convergence of life-history phenotypes across slopes. Here, we characterize the life-history phenotypes of Rivulus from north-slope communities by measuring number of eggs, egg weight, reproductive allotment, reproductive tissue weight, and size at maturity. We find similar patterns of life-history divergence across analogous predator communities. Between slopes, minor differences in Rivulus life-history traits exist and one potential cause of these differences is the abundance of Macrobrachium prawns in north-slope rivers..
Strogolova, V.
Furness, A.
Robb-McGrath, M.
Garlich, J.
Stuart, R.A.
(2012). Rcf1 and Rcf2, members of the hypoxia-induced gene 1 protein family, are critical components of the mitochondrial cytochrome bc1-cytochrome c oxidase supercomplex. Mol cell biol,
Vol.32
(8),
pp. 1363-1373.
show abstract
full text
We report that Rcf1 (formerly Aim31), a member of the conserved hypoxia-induced gene 1 (Hig1) protein family, represents a novel component of the yeast cytochrome bc(1)-cytochrome c oxidase (COX) supercomplex. Rcf1 (respiratory supercomplex factor 1) partitions with the COX complex, and evidence that it may act as a bridge to the cytochrome bc(1) complex is presented. Rcf1 interacts with the Cox3 subunit and can do so prior to their assembly into the COX complex. A close proximity of Rcf1 and members of the ADP/ATP carrier (AAC) family was also established. Rcf1 displays overlapping function with another Hig1-related protein, Rcf2 (formerly Aim38), and their joint presence is required for optimal COX enzyme activity and the correct assembly of the cytochrome bc(1)-COX supercomplex. Rcf1 and Rcf2 can independently associate with the cytochrome bc(1)-COX supercomplex, indicating that at least two forms of this supercomplex exist within mitochondria. We provide evidence that the association with the cytochrome bc(1)-COX supercomplex and regulation of the COX complex are a conserved feature of Hig1 family members. Based on our findings, we propose a model where the Hig1 proteins regulate the COX enzyme activity through Cox3 and associated Cox12 protein, in a manner that may be influenced by the neighboring AAC proteins..
Patterson, B.M.
Furness, A.J.
Woodbury, R.J.
(2012). In Situ Calibration Checking Technique for Permanently Installed Oxygen Probes in the Vadose Zone. Vadose zone journal,
Vol.11
(3),
pp. vzj2011.0157n-vzj2011.0157n.
Patterson, B.M.
Shackleton, M.
Furness, A.J.
Bekele, E.
Pearce, J.
Linge, K.L.
Busetti, F.
Spadek, T.
Toze, S.
(2011). Behaviour and fate of nine recycled water trace organics during managed aquifer recharge in an aerobic aquifer. Journal of contaminant hydrology,
Vol.122
(1-4),
pp. 53-62.
Pitoi, M.M.
Patterson, B.M.
Furness, A.J.
Bastow, T.P.
McKinley, A.J.
(2011). Fate of N-nitrosomorpholine in an anaerobic aquifer used for managed aquifer recharge: A column study. Water research,
Vol.45
(8),
pp. 2550-2560.
Patterson, B.M.
Shackleton, M.
Furness, A.J.
Pearce, J.
Descourvieres, C.
Linge, K.L.
Busetti, F.
Spadek, T.
(2010). Fate of nine recycled water trace organic contaminants and metal(loid)s during managed aquifer recharge into a anaerobic aquifer: Column studies. Water research,
Vol.44
(5),
pp. 1471-1481.
Patterson, B.M.
Annable, M.D.
Bekele, E.B.
Furness, A.J.
(2010). On-line groundwater velocity probe: Laboratory testing and field evaluation. Journal of contaminant hydrology,
Vol.117
(1-4),
pp. 109-118.
WRIGHT, G.
SANDERSON, J.M.
FURNESS, A.
(1978). PULSATILE PUMPS FOR OPEN-HEART SURGERY. Lancet,
Vol.1
(8057),
pp. 217-2.
Chisholm, J.
Corley, E.
Furness, A.
Schmitt, A.
The role of systemic therapy in paediatric cutaneous melanoma: a review. Pediatric medicine,
.
full text
Dekker, M.L.
Hagmayer, A.
Leon-Kloosterziel, K.M.
Furness, A.I.
Pollux, B.J.
High Degree of Multiple Paternity and Reproductive Skew in the Highly Fecund Live-Bearing Fish Poecilia gillii (Family Poeciliidae). Frontiers in ecology and evolution,
Vol.8.
Alotaibi, M.D.
Patterson, B.M.
McKinley, A.J.
Reeder, A.Y.
Furness, A.J.
Benzotriazole and 5-methylbenzotriazole in recycled water, surface water and dishwashing detergents from Perth, Western Australia: analytical method development and application. Environmental science: processes & impacts,
Vol.17
(2),
pp. 448-457.
show abstract
A simplified analytical method was developed and used to assess the occurrence of benzotriazole and 5-methyl benzotriazole and removal rates in various Western Australian environmental water samples.
.