The Characterization of T-Cell Manufacturing For Adoptive T-Cell Therapies

<p>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<em> </em>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2019

Authors dc:creator

• ALPERT, amir
• <p>https://orcid.org/0000-0002-1274-1813</p>

Contributors dc:contributor

• Greg Lizee
• Michael Curran
• Michelle Barton

• T cell
• CD28
• TCR
• Adoptive
• Cell Therapy
• ACT
• Biotechnology
• Immunology and Infectious Disease

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/946

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1991