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.