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Lena Gamboa
BME PhD Defense Presentation
Date:2021-12-13
Time: 11:00 AM
Location / Meeting Link: IBB Suddath Seminar Room 1128 // Virtual Link: https://bluejeans.com/998051859/1963
Committee Members:
Gabe Kwong, Ph.D. (Advisor) Costas Arvanitis, Ph.D. James Dahlman, Ph.D. Andrés J. García, Ph.D. Haydn Kissick, Ph.D.
Title: Programming synthetic T cell immunity against solid tumors
Abstract: T cells engineered with chimeric antigen receptors (CARs) have resulted in durable remission for patients with certain B cell malignancies, yet their inability to mount effective antitumor responses against solid tumors underscores the need to devise strategies that safely and potently enhance T cell immunity. This thesis focuses on two major challenges that contribute to the poor clinical responses of engineered T cell therapies for solid tumors. First, there is a limited ability to spatially control the activation and repression of immunomodulatory genes within engineered T cells in vivo. To fully direct T cell activity without widespread systemic toxicities and overcome barriers like poor tumor infiltration, proliferation, and cytotoxicity, the ability to locally turn genes on or off is needed. This includes activation of immunostimulatory genes (e.g., chemokines, cytokines) and repression of inhibitory signals (e.g., immune checkpoint pathways). Second, tumor antigens that are selectively and uniformly expressed by malignant cells are rare. Heterogenous antigen expression within a tumor, interpatient variation in antigen expression, and the expression of tumor-associated antigens (TAAs) by healthy tissue hinders the ability of T cells to safely and effectively eliminate malignant cells. As CAR T cells are developed for more cancer indications, developing strategies that direct T cell activity with spatial precision and promote recognition of tumor cells will be critical to achieve effective antitumor responses. Toward this end, the major goal of this thesis is to potentiate antitumor immunity by in situ programming of T cell activity. First, in Aim 1, I integrate heat as a remote trigger with CRISPR-dCas9 to enable remote control of transcriptional activity. In contrast to chemical or optical cues, pulses of heat can be delivered noninvasively with millimeter precision and at depth to anatomical sites by approaches such as infrared light and high-intensity focused ultrasound. I show that thermal control of dCas9 variants enables tunable and conditional control of both transcriptional activation and repression. Then, in Aim 2, to enable T cell recognition of solid tumors lacking targetable antigens, I developed synthetic antigens to trigger tumor recognition and subsequent elimination by CAR T cells. Unlike TAAs, synthetic antigens are orthogonal to endogenous proteins to minimize off-tumor toxicity, and their small genetic footprint facilitates direct delivery to the tumor by viral and nonviral approaches. Adoptive transfer of CAR T cells to mice bearing synthetic antigen-treated tumors reduced tumor burden in multiple syngeneic models of cancer, improved survival, induced epitope spread, and protected against tumor rechallenge. Moving forward, in situ programming of T cells provides an opportunity to augment antitumor responses and address barriers that limit the broad clinical translation of T cell therapies.
