Lung cancer has is responsive to immunotherapy due to the large number of mutations it harbors, which serve as foreign antigens detected by the immune system. However, a majority of patients still does not respond to these therapies. Tumor heterogeneity contributes to the lack of success of these therapies, by ensuring different cells within the same tumor present different antigens. This limits the ability of T cells to kill all tumor cells, rather confining them to the subset which express a specific antigen. One reason for this is the non-essential nature of the mutations from which these antigens are derived, which allows a tumor to lose these antigens as it evolves without serious conse...

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Lung cancer has is responsive to immunotherapy due to the large number of mutations it harbors, which serve as foreign antigens detected by the immune system. However, a majority of patients still does not respond to these therapies. Tumor heterogeneity contributes to the lack of success of these therapies, by ensuring different cells within the same tumor present different antigens. This limits the ability of T cells to kill all tumor cells, rather confining them to the subset which express a specific antigen. One reason for this is the non-essential nature of the mutations from which these antigens are derived, which allows a tumor to lose these antigens as it evolves without serious consequence. Importantly, tumors develop from an accumulation of mutations, some of which provide a critical survival advantage (ie. driver mutations). Because of their role and nature, driver mutations are therefore more prevalent across patients, and homogeneously-detected throughout a tumor. Therefore, therapeutically targeting antigenic driver mutations could offer greater promise and extend to a large proportion of patients harboring these mutations across lung cancer and many other cancer types. EGFR is a growth factor receptor which often acquires mutations in lung cancer, with 10-50% of lung cancer patients harboring such mutations. This provides a unique opportunity to therapeutically target antigens derived from these mutations using T cells. We have previously confirmed that mutations in EGFR result in antigens visible to T cells through their receptor and lead to tumor killing. Therefore, in this proposal, we will develop T cell therapies by engineering their receptors to recognize antigens derived from EGFR mutations and kill tumor cells. These therapies could benefit a large proportion of cancer patients harboring these mutations. Importantly, this will result in an off the shelf T cell therapy for the majority of cancer patients harboring EGFR mutations.

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