#MRFResearchWednesday: Zachary Walsh, 2025 Medical Student Award

Guest Blog SUBMITTED BY
Zachary Walsh
“Leveraging T Cell Genetic Variants to Enhance Melanoma Immunotherapies”
T cell immunotherapies, which harness the power of a patient’s own immune system to target and eliminate tumor cells, are becoming an increasingly promising treatment approach for melanoma, including for patients who do not respond to immune checkpoint inhibitors. However, many melanoma patients experience relapse or poor response after receiving these therapies, which highlights the critical need to engineer improved T cell therapies. As part of the Izar group at Columbia, my work aims to address this important gap.
Remarkably, both pre-clinical and population genetics studies show that single-base DNA changes in our genetic code can dramatically impact a T cell’s 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 at once, accelerating our ability to uncover “needle in a haystack” mutations which enhance their ability to kill melanoma cells. In these genetic “screens,” we discovered several mutations in the AKT1 gene which augmented T cell killing of melanoma cells, providing a promising engineering approach to generate a more robust anti-cancer T cell product.
Thanks to generous funding from the MRF, we will now be able to study these AKT1-mutant T cells in greater depth and extensively evaluate their anti-melanoma activity in a panel of clinically relevant models. First, we aim to understand precisely why they enhance T cell killing of melanoma, giving us better insight into how to further improve future therapies. Next, we are working to test these AKT1-mutant T cells in a clinically relevant mouse model of T cell immunotherapy for melanoma – a closer approximation of efficacy in patients. Finally, we are studying whether these AKT1-mutant T cells can overcome a common mechanism of immunotherapy resistance in melanoma – loss of a protein called CD58, which our group has previously uncovered. We believe that completion of this work has the potential to inform a clinically relevant engineering strategy to improve immunotherapy responses for melanoma patients.