Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Adoptive cell transfer (ACT) using T cells engineered to express tumor-specific T cell receptors (TCR) holds great promise in treating cancer patients. ACT involves the in vitro generation of large numbers of tumor-specific T cells, which are then administered back to the patient, to establish an in vivo response and effective tumor control. Our lab conducted a phase I clinical trial in which metastatic melanoma patients received systemic infusions of autologous T cells transduced to express a tyrosinase-specific TCR (TIL 1383I). We observed tumor regression in one of seven patients and the development of vitiligo, indicative of T cell-mediated killing of melanocytes, in two of seven patients. Our findings demonstrate that the ACT of TCR gene-modified T cells has the potential to eliminate tumors, but the modest number of patients responding to therapy emphasizes the need for improvement. In the studies presented in this dissertation, we evaluated the intratumoral delivery of TIL 1383I TCR transduced T cells in a widely used B16 mouse melanoma model. We employed an alternative strategy and expressed the TIL 1383I TCR on allogeneic, as opposed to syngeneic, donor T cells, to attempt to counteract the suppressive tumor microenvironment. We demonstrated that intratumoral treatment with TIL 1383I TCR allogeneic T cells extended survival and suppressed tumor growth in mice more effectively than treatment with TIL 1383I TCR syngeneic T cells. Tumors treated with TIL 1383I TCR allogeneic T cells exhibited greater accumulation of antigen cross-presenting dendritic cell subsets, as well as increased T cell activation, in the tumor and tumor draining lymph nodes. TIL 1383I TCR allogeneic T cell treatment generated endogenous tumor-specific T cells that prevented the development of distant, untreated tumors. Furthermore, the addition of immune checkpoint inhibitors promoted tumor clearance and enhanced protection in mice treated with TIL 1383I TCR allogeneic T cells. Intratumoral delivery of allogeneic TCR gene-modified T cells can improve clinical responses and expand the available tumor antigen targets, without compromising safety, by avoiding systemic administration.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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