Date of Award
2024
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Yina Huang
Abstract
Responsiveness to chimeric antigen receptor (CAR) T cell therapy correlates with CAR T cell expansion and persistence in vivo. Multiple working strategies improve CAR T cell persistence by increasing stem-like properties or by sustaining CAR T cell activity with combination therapies. Herein, we describe the intrinsic ability of CAR T cells to differentiate into memory T cells, the effect of cytokine armoring, and neoadjuvant CD4 depletion therapy on CAR and tumor-specific endogenous memory T cells. TRP1-specific CAR T cells alone or in combination with Super2 + IL-33 (S233) armoring and/or CD4 depletion therapy were evaluated in the immunocompetent B16F10 melanoma model. We characterized CAR and endogenous tumor-specific memory T cell precursors, the establishment of circulating (TCIRC) and resident (TRM) memory T cell subsets, and their response to secondary tumors. TRP1- specific CAR T cells had no effect on primary B16F10 tumor growth in immunocompetent mice unless it was combined with S233 armoring or CD4 depletion therapy. Conventional (unarmored) CAR T cells expressed a stem-like phenotype in the tumor-draining lymph node (TDLN) and differentiated into CAR TCIRC memory cells in lymphoid organs and into CAR TRM cells in the skin. In contrast, S233-armored CAR T cells exhibited an activated effector phenotype and differentiated inefficiently into CAR effector (TEM) and central (TCM) memory T cells. Combining CD4 therapy with CAR T cells increased CAR TCIRC memory T cells but was unable to induce CAR TRM cells. Either CD4 depletion therapy or S233-armored CAR T cells induced activation of tumor-specific endogenous T cells that differentiated into both TCIRC and TRM memory T cells. CD4 depletion and S233-armored CAR T cell combination therapy synergized to increase endogenous TCIRC and TRM memory T cells.
Recommended Citation
Mohamed, Asmaa, "Driving CARs down memory lane: uncovering CAR memory T cell and antigenspecific endogenous T cells importance in durable responses against melanoma" (2024). Dartmouth College Ph.D Dissertations. 320.
https://digitalcommons.dartmouth.edu/dissertations/320
