Investigating mechanisms of CARD11 mutants in enhanced anti-tumor immunity and T cell fitness (For Kathleen Cheng)

Project Summary/Abstract Adoptive cellular therapies (ACTs) have made remarkable advances in the treatment of hematological malignancies. However, remarkable outcomes are confined to a subset of patients with blood cancers and have not been achieved in individuals with solid tumors, which account for 90% of adult cancers. Therefore, innovative

approaches to overcome these limitations are essential to address the substantial unmet need for effective cellular therapies. We hypothesize that the answer may come from an unlikely source, T cell neoplasms. T cells in T cell neoplasms have developed genetic means to improve T cell fitness and overcome some of the same

obstacles faced by therapeutic T cells. Our group has pioneered a pipeline using lymphoid neoplasm mutations as a method to address the obstacles faced by therapeutic T cells. We found a novel gene fusion, CARD11- PIK3R3, that dramatically increases accumulation, effector function, and anti-tumor efficacy of adoptively

transferred cells in an antigen dependent manner in multiple TCR-transgenic T cell models. These results have been demonstrated in fully immunocompetent murine models without lymphodepletion, with no evidence of lymphomagenesis or toxic effects. Preliminary data from our group suggests that these fusion expressing cells

have unique cytokine profiles and increased effector function in vitro. However, the mechanisms by which they enhance anti-tumor immunity in vivo is still unclear. Therefore, in this proposal we aim to mechanistically dissect the pathways that govern this unique phenotype and strong anti-tumor immunity. Our preliminary in vivo data

suggest that these fusion expressing cells have increased stemness, polyfunctionality, and are able to resist T cell exhaustion. In Aim 1, we will utilize in vivo models and single cell -omics to determine the transcriptional, epigenetic and metabolic mechanisms that allow CARD11-PIK3R3 expressing cells to resist exhaustion. In Aim

2, we will Identify how CARD11-PIK3R3 T cells affect the immune populations in the tumor microenvironment to promote anti-tumor immunity, and determine whether those populations are necessary and sufficient to increase therapeutic efficacy of the fusion. Preliminary data form our lab has already shown enhanced recruitment of certain

cell populations in CARD11-PIK3R3 treated tumors. Using multiple transgenic mouse models to selectively deplete certain cell population, we will uncover important interactions in the tumor microenvironment. My overall career goal is to become a successful, independent physician-scientist. The rigorous training plan proposed in this fellowship

will allow me to achieve that goal by gaining research skills and knowledge in cellular immunology, cancer signaling pathways, epigenetics, and metabolism. I will be mentored by Dr. Jaehyuk Choi, an expert and role- model physician-scientist, who has devised a rigorous training plan to develop all necessary research skills,

communication skills, and promote my professional development. This fellowship will broaden our understanding of T cell phenotypes and signaling, and identify potential novel therapeutic strategies to improve adoptive cellular therapies, as well as provide the necessary foundation for my future career as a physician-scientist.