Author ORCID Identifier

https://orcid.org/0000-0002-1274-1813

Date of Graduation

5-2019

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Greg Lizee

Committee Member

Michael Curran

Committee Member

Michelle Barton

Committee Member

Vidya Gopalakrishnan

Committee Member

Chantale Bernatchez

Abstract

Adoptive T-cell therapy using genetically modified T cells has emerged as a potential therapeutic option for several malignancies. Central to the production of the cellular therapy is the manufacturing using a stimulation, genetic engineering, and expansion methodology. Within this framework, there is a delicate balance between expansion of the cells to a therapeutically relevant dosage and the need to retain the proliferative potential of the ‘living drug’. I show that as T-cells are expanded for elongated periods of time, they lose their proliferative potential and become functionally senescent despite the presence of multiple proliferative cytokines. In addition, I show that expression of CD28 correlates with multiple manufacturing metrics, including final T-cell fold expansion. I propose that the loss of CD28 expression creates a T-cell expansion bottleneck in which certain T-cell clones are heavily favored compared to others during manufacturing. Compounding the multiple correlations, I performed a meta-analysis of available clinical trial data to show that younger patients appear to respond better to T-cell manufacturing involving CD28 costimulation, while older patients appear to respond better to T-cell manufacturing lacking CD28 costimulation.

Keywords

T cell, CD28, TCR, Adoptive, Cell Therapy, ACT

Available for download on Saturday, May 09, 2020

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