Grant: Project Grant

Over the past decade, immunotherapy has revolutionized the treatment of many cancers. Patients with metastatic melanoma have benefited from a new class of drugs called immune checkpoint inhibitors (ICI), which have increased the fraction of patients surviving 10 years or more from <10% to over 40% today. Despite this progress, help is urgently needed for those patients who are failed by ICI. Recently, success has been demonstrated for an approach in which T cells (a type of immune cell) are isolated from the patient's tumour, expanded to large numbers in the lab, and reinfused into the patient's bloodstream (after the patient has undergone so-called "pre-conditioning chemotherapy") along with a growth factor called Interleukin-2 (IL-2). This treatment, called "Tumour-Infiltrating Lymphocyte" (TIL) therapy, induces objective responses in about 40% of melanoma patients, including those failed by ICI therapy, with about 10% of patients achieving complete remissions. While this is an exciting advance, there is a pressing need to improve the efficacy and safety of this approach. We have developed an innovative genetic engineering technology that eliminates the need for pre-conditioning chemotherapy and IL-2 (and the significant toxicities they bring) while also inducing unprecedented levels of T cell expansion and anti-tumour activity in mice, leading to complete and durable tumour regression in the majority of animals. We propose to (1) identify the factors that underlie the remarkable effectiveness of this technology in a mouse melanoma model; (2) try to improve the technology further by incorporating other signals beyond IL-2; and (3) "test drive" this technology in lab studies using T cells from human melanoma patients. Our overarching goal is to create a safe, effective and feasible form of TIL therapy that is ready for clinical trials in Canada. While this proposal is focused on melanoma, our findings will have broad relevance to other types of cancer.