Immune checkpoint inhibitors in combination with oncolytic virotherapy delivered by isolated limb perfusion as a means of enhancing systemic tumour-specific immunity in extremity sarcoma
Isolated limb perfusion (ILP) with melphalan and tumour necrosis factor α (TNFα) achieves limb salvage rates of up to 90% in patients with advanced extremity sarcoma. However, it is a regional treatment and has no effect on the development and progression of disseminated disease. Oncolytic virotherapy (OV) is able to kill tumour cells directly but also has the potential to prime the immune system to target local and disseminated disease.
The efficacy of OV may be limited by tumour mechanisms of immune evasion. Biological agents targeting immune checkpoints, such as monoclonal antibodies against PD-1/PD-L1, aim to combat adaptive immune resistance in tumours and have shown promising results in clinical trials in other pathologies. Early clinical trials of these agents in sarcoma are currently underway.
Previous work within our team, using an established model of ILP in rodent extremity fibrosarcoma, has demonstrated prolonged local disease control when OV (vaccinia virus) is added to standard ILP combined with tumour excision and adjuvant radiation (Figures 1 & 2). Although local disease control was achieved, disseminated disease developed in some animals, mimicking the clinical picture of extremity sarcoma in humans. When surviving animals were re-implanted with the original tumour cell line, the rate of tumour growth was slower compared to controls suggesting that some degree of anti-tumour immunity had developed.
We hypothesise that the addition of immune-modulatory agents to our established treatment protocol will induce a greater degree of anti-tumour immunity, improving control of local and disseminated disease.
Figure 1. Cartoon schematic of our animal model of isolated limb perfusion in extremity sarcoma (click to show full size).
Figure 2. The addition of oncolytic virotherapy to isolated limb perfusion results in delayed tumour growth (a) and prolonged survival (b) (click to show full size).