Genomics Project

Establishing TIL Therapy for Immunotherapy-Resistant Melanoma

Media/Lay Summary

The project proposed in this grant application focuses on improving outcomes for patients who have failed current therapies for advanced (metastatic) melanoma. Our research program focuses on pioneering cell therapy for melanoma, and in the longer term for other cancers. The program will bring to WA a clinically developed therapy based on the infusion of the patient’s own immune cells to fight cancer, and cutting-edge research to further improve this therapy.

Synopsis of the Grant Proposal

Melanoma is a deadly form of skin cancer with an increasing incidence rate worldwide. Australia currently has the highest incidence of melanoma, which accounts for an estimated annual healthcare cost burden of $201 million1. In recent years,
advancements in our understanding of the genetics and immunology of melanoma have led to the development of novel molecular targeted and immune-based therapies for a subset of patients. Unfortunately, these treatments are often associated with debilitating and persistent side-effects. Moreover, around 50% of patients will not derive clinical benefit and succumb to the disease.

The Western Australia Melanoma Initiative (WAMI) is a research collaborative comprising basic and clinical researchers from WA, as well as their national and international collaborators. The clinical needs of our consumer representatives with lived experience of melanoma drives WAMI research agenda and the focus of this grant application. Our project aims to improve the outcomes of patients not benefiting from current therapies. WAMI will build upon current areas of excellence in melanoma research in WA, focusing on consolidating existing biobanks and developing an analytical pipeline to provide detailed molecular profiling for translational clinical studies.

WAMI’s overarching themes here are: (i) implement adoptive cell therapy with tumour infiltrating lymphocytes (TILs) in WA and (ii) use advanced animal models, fundamental research and gene therapeutics to improve TIL and other cell therapies. Notably, TIL therapy is an effective form of cellular immunotherapy currently unavailable in Australia. The establishment of clinical experience in cell therapy for melanoma, and our innovative platform for improving and delivering additional cell therapies, will improve the lives of patients and enable translation also for patients with other solid tumours.

A special focus of WAMI is to identify which patient is most likely to require TIL therapy. By biobanking tumours and blood before and after immune checkpoint inhibitor therapy and TIL therapy, biomarkers that can help with patient stratification will be made clinically useful.

Outcomes for Cancer

A major goal of WAMI is to provide patients in WA with TIL therapy, as a critical therapeutic option for patients unlikely to respond to standard immunotherapy funded by the state healthcare sector. This treatment is already available in certain countries; for example, in Denmark and The Netherlands it is offered to patients with ICI resistant melanoma free of charge. Besides democratising access, our point-of-care manufacturing of TILs will also provide a platform for initiation of clinical trials seeking to improve TIL therapy and engineered novel CAR T-cell therapies. We will offer the treatments to patients from other states through our clinical collaborators and instigate national collaborative projects to leverage further funds to enable the expansion of the program Australia-wide.

Early in the treatment trajectory, patient samples will be collected for detailed molecular analysis and stratification of risk of progression, probability of response to standard immunotherapy and risk of developing irAEs. The patient’s tumour-immune infiltrates will be stored and used to produce cell therapy preparations for ACT. Patients with ICI resistance profiles will be triaged for novel clinical trials championed by WAMI clinicians and collaborators.

In addition, our proposed approach involving parallel discovery programs will enable the identification of novel and improved cell therapies. These will be tested in animal models, including in-house generated PDX models. These types of experiments will provide solid evidence on the efficacy needed to start clinical trials.

Overall, we envisage that our personalised approach, bolstered by cutting-edge technology and expertise, will deliver significant impact and improved survival for melanoma patients. Application of our expertise to other cancers will support similar research programs helping to improve cancer survival overall.