Date of Award

Spring 4-22-2024

Embargo Period

4-23-2026

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Richard O'Neil

Abstract

In the past four decades, immunotherapies have revolutionized cancer treatment, offering new hope for patients with various malignancies. Among these groundbreaking therapies is adoptive T cell therapy (ACT), which involves enriching and expanding autologous tumor-reactive T cells for reinfusion into the patient, capitalizing on the potent ability of T cells to target tumors. This powerful approach can induce complete durable responses in subsets of patients. However, several aspects of adoptive T cell therapy can be improved warranting further development in the context of recent technological advances. A nearly ubiquitous practice in T cell adoptive transfer protocols is lymphodepleting pre-conditioning, which often leads to clinically significant side effects that limit utility and adoption of ACT. Specifically, lymphodepleting regimens used clinically lead to pan-cytopenia, immune suppression, and reactive myelopoiesis potentially undermining the therapeutic index of ACT. To address these challenges, we embarked on studies aimed at investigating the mechanisms underlying effective engraftment in ACT, hypothesizing that such mechanisms might be cell autonomous and not reliant on the host's lymphodepleted immune status. Leveraging mouse models, we focused on exploring the role of Stat5 signaling during T cell adoptive transfer. Remarkably, through transient expression of a constitutively active mutamer of Stat5 during the adoptive transfer process, we successfully obviated the need for lymphodepletion prior to transfer. Functional assays revealed minimal differences in the function and phenotype of engrafted T cells compared to those transferred after conventional lymphodepletion. Moreover, bypassing lymphodepletion reduced peripheral IL-6 spikes and signatures of suppressive myeloid cells typically associated with poor clinical responses. Our findings shed light on a cell-autonomous mechanism mediated by transient Stat5 signaling during engraftment, which has lasting effects on T cell function. Thus, this dissertation provides compelling evidence that the efficacy of adoptive T cell therapy can be substantially improved by eliminating lymphodepleting protocols entirely and replacing them with mRNA transfection of T cells with transcripts encoding active Stat5. This paradigm shift holds promise for advancing the field of ACT and improving outcomes for patients.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Thursday, April 23, 2026

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