Leveraging T cell genetic variants to enhance melanoma immunotherapies

T cell immunotherapies, which harness the power of a patient’s own immune system to eliminate tumor cells, are becoming an increasingly promising treatment avenue for melanoma, including patients who do not respond to existing immune checkpoint inhibitors. However, many melanoma patients experience relapse or poor response after receiving these therapies, underscoring the critical need to engineer improved T cell therapies. Remarkably, both pre-clinical and population genetics studies show that single mutations in T cell genes can dramatically impact T cell behavior and thus have the potential to powerfully modulate T cell therapies. To this end, we developed methods to precisely engineer thousands of mutations in human T cells and identify mutations which enhanced their ability to kill melanoma cells. In these genetic “screens,” we discovered several mutations in the AKT1 gene which significantly improved T cell killing of melanoma cells in preliminary studies, providing a promising engineering approach to generate a more robust T cell product. The first aim of this work is to study these AKT1 mutations in greater depth to understand the mechanism by which they enhance T cell anti-melanoma activity. We will also test these AKT1-edited T cells in a clinically relevant mouse model of T cell immunotherapy for melanoma – a closer approximation of efficacy in patients. The second aim of this work is to determine whether these AKT1-edited T cells are able to overcome a common mechanism of immunotherapy resistance in melanoma – loss of a protein called CD58 – in analogous pre-clinical models to our first aim. Completion of this proposed work has the potential to inform a clinically relevant engineering strategy to improve immunotherapy responses for melanoma patients.