Date of Award

2017

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Chrystal Paulos

Second Advisor

Carl Atkinson

Third Advisor

Luca Gattinoni

Fourth Advisor

Zihai Li

Fifth Advisor

Satish N. Nadig

Sixth Advisor

Juan Varela

Abstract

The development of immunotherapies over the last three decades has dramatically improved treatment for late stage cancers. Among these therapies is adoptive T cell therapy (ACT), which enriches and expands autologous tumor- reactive T cells for reinfusion to the patient. ACT has exploited the power of T cells to exert long-term immunity providing unprecedented responses, including complete remissions and cures. Three major benefits of ACT have emerged since the early trials: 1), ACT provides a window for preconditioning the patient. This allows transferred T cells to engraft in large numbers, become functionally enhanced, and be free of immunosuppressive pressure. 2), ACT allows for the selection of T cells with superior antitumor qualities for treatment. 3), The ex vivo expansion period allows for further manipulation of those T cells to enhance their antitumor capacity. Also, an overarching theme in ACT is that complete and durable responses are possible in patients who receive T cells capable of long- term memory responses. We examined the impact of each element of the ACT regimen on the memory of T cells including how preconditioning influences memory and function, the advantage of employing IL-17 producing CD4+ T cells (Th17) cells with durable memory properties, and how to endow CD8+ T cells with improved memory capacity through blockade of the PI3K pathway. We discovered we can ex vivo prime T cells with IL-12 to mimic the potentiating effect of an activated innate immune system to improve the longevity of antitumor immunity and reduce the dose of total body irradiation (TBI). We also report that Th17 cells naturally express stem memory, which allows for expansion to high numbers of durable effectors and long-lasting immunity against tumors. Finally, peripheral T cells genetically redirected against tumors with chimeric antigen receptors (CAR T cells) can be enhanced by pharmaceutical blockade of PI3K endowing a durable memory phenotype that controls tumor after conventional CAR T cells fail. Thus, this dissertation provides evidence that at each step in the ACT protocol, T cells can be selected, or enhanced to exert powerful memory immunity that translates into durable responses in patients with late stage malignancies.

Rights

All rights reserved. Copyright is held by the author.

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