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