Professor Alan Melcher, Translational Immunotherapy Team
Our group is interested in translational research linking laboratory findings to early clinical application, with a particular focus on therapeutic anti-cancer (‘oncolytic’) viruses (OV).
OV were initially developed as direct cytotoxic agents, to specifically infect, replicate within, and kill cancer cells. However, it has become increasingly clear that OV work more by stimulating an immune response against the tumour — i.e. they are a form of immunotherapy.
We work on a range of clinical grade viruses (reovirus, herpes, vaccinia, coxsackie and maraba), and have shown, using pre-clinical murine models, human in vitro immune assays and readouts from early, biological endpoint translational clinical trials in patients, that OV activate both innate and adaptive anti-tumour immunity.
Combining OV with other immune modulators, such as granulocyte-macrophage colony-stimulating factor, or checkpoint inhibitors can further enhance their efficacy. We are taking these pre-clinical findings back into the early clinical trial setting using an iterative ‘bench to bedside and back again’ approach.
While the only current clinically approved oncolytic virus (a herpes virus encoding GMCSF) is given by direct intratumoural injection, we believe that systemic administration of viruses is far more practical for widespread clinical application. We are therefore focusing on intravenous OV delivery, in both the laboratory and the clinic, and have found, paradoxically, that anti-viral antibodies can actually enhance therapy by facilitating viral carriage by immune cells in the blood (specifically monocytes), to the tumour site.
We have confirmed OV access to tumours in patients following intravenous injection in patients with both colorectal cancer metastatic to the liver, and brain tumours (recurrent high grade gliomas or brain metastases). This has been done using ‘window of opportunity’ studies, giving OV prior to planned surgical resection of tumours as part of standard clinical care.
We are also testing incorporation of pre-clinically optimized systemic OV treatment with clinical standard of care treatments (immune checkpoint inhibition, radiotherapy or steroids), to ensure that our novel research findings are practically deliverable into the real clinical world, and to facilitate rapid benefits for patients with melanoma, head and neck, brain, and potentially other tumours.