Tumor-Localized Control of CAR T Cells to Potentiate Solid Tumor Immunotherapy
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Zamat, Ali
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Abstract
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of several hematological malignancies, achieving durable remissions in patients with B cell cancers. However, its efficacy against solid tumors remains limited due to challenges such as antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and the scarcity of tumor-specific antigens (TSAs). These obstacles not only impede T cell infiltration, activation, and persistence within tumors but also increase the risk of off-tumor toxicity due to the expression of tumor-associated antigens (TAAs) by healthy tissues. Addressing these barriers is crucial to unlock the full potential of CAR T cell therapy for solid tumor treatment. This thesis focuses on developing tumor-localized strategies to potentiate CAR T cell-mediated immunity against solid tumors.
I first develop thermal gene switches that enable remote control of gene expression in primary human and murine T cells in response to mild hyperthermia. By integrating these thermal switches with CAR T cells engineered to produce immunomodulators such as interleukin-15 superagonist (IL-15 SA) and bispecific T cell engagers (BTEs), I demonstrate that localized photothermal heating triggers the expression of therapeutic proteins within the TME to enhance intratumoral activity of CAR T cells. I then demonstrate that surface conjugation anisotropic gold nanoassemblies (GNAs) to thermal sensitive CAR T cells enables multimodal photoacoustic imaging and photothermal therapy to non-invasively monitor trafficking of CAR T cells and enhance antitumor activity against heterogeneous solid tumors. Next, to combat the immunosuppressive effects of the TME, I demonstrate that focused ultrasound-mediated hyperthermia locally triggers the expression of BTEs to redirect CAR T cell cytotoxicity towards the immunosuppressive brain tumors by depleting myeloid derived suppressor cells (MDSCs), leading to significant tumor regression in glioblastoma. Finally, I engineer synthetic antigens to sensitize solid tumors to CAR T cell therapy and bypass the need for tumor antigen discovery. I deliver VHH as an mRNA-encoded synthetic antigen using lipid nanoparticles (LNPs) which can be targeted by αVHH CAR T cells to significantly reduce tumor burden, mitigate antigen escape, and improve survival. Collectively, this thesis provides a foundation for tumor-localized control of CAR T cells to improve therapeutic responses against solid tumors.
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2024-12-06
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Dissertation (PhD)