Claire McClain
BME PhD Defense Presentation

Date: 2024-11-06
Time: 3:00PM-5:00PM
Location / Meeting Link: IBB Suddath Seminar Room 1128, https://gatech.zoom.us/j/97889560599

Committee Members:
Chrystal M. Paulos PhD; Erik C. Dreaden PhD; Krishnendu Roy PhD; Melissa L. Kemp PhD; Susan N. Thomas PhD (Advisor)


Title: Locoregional and systemic immunomodulation with intratumoral TCR agonism

Abstract:
Immunotherapies that modulate a patient’s endogenous adaptive immune response to elicit their effects that range from adoptive cell therapies (ACT) to immune checkpoint blockade (ICB) are now mainstays of clinical management of most malignancies. However, rates of patient response to immunotherapeutic regimens remain disappointingly low, a result thought to reflect a lack of a robust tumor antigen-specific lymphocyte pool in the patient. Therefore, employing off the shelf, potent T cell modulators that leverage the immune system’s intrinsic anti-tumor mechanisms to quickly to combat tumor progression is advantageous. Here I demonstrate a single dose of aCD3 induces potent tumor control in a B16F10 orthotopic tumor model and is well tolerated. Not only does this antigen agnostic TCR agonism strategy result in the mobilization of therapeutic T cell populations into the circulation and subsequent increased tumor infiltration, but it also synergizes with current ICB immunotherapies, namely aPD-1, improving overall survival. Further, therapy was not restricted to an intratumoral route of administration, where tumor draining lymph node (TDLN) directed administration of aCD3, also resulted in the expansion of effector CD8 T cells into the circulation and enhanced tumor infiltration. This minimally invasive therapeutic strategy induces remodeling of CD8 T cell subsets in both the TDLN and NDLN indicating both local and systemic immune modulation. The quality of CD8 T cell subsets mobilized into the circulation has strong implications for the efficacy of cancer immunotherapies, therefore understanding the flux of key immune populations from lymphoid tissues through the circulation and into the tumor, is essential in developing therapeutic modalities to ameliorate patient outcomes.