Tethered Il-15 to Augment The Therapeutic Potential of T Cells Expressing Chimeric Antigen Receptor: Maintaining Memory Potential, Persistence, and Antitumor Activity

<p><strong>Tethered IL-15 to augment the therapeutic potential of T cells expressing chimeric antigen receptor: Maintaining memory potential, persistence, and antitumor activity</strong></p> <p>Adoptive immunotherapy can retarget T cells to CD19, a tumor-associated antigen (TAA) expressed on B-cell malignancies, by the expression of a chimeric antigen receptor (CAR). Infusion of CAR-modified T cells for the treatment B-cell malignancies has demonstrated promise in preclinical and clinical trials. These data highlight the ability of infused CD19-specific T cells to be synchronously activated by large burdens of CD19⁺ leukemia and lymphoma. This can lead to dramatic antitumor effects, but also exposes the recipient to toxicity associated with tumor-cell lysis and cytokine storm. Clinical trials will now be addressing the targeting of minimal burdens of CD19⁺ malignancy as patients are enrolled earlier in their disease course and receive concomitant chemotherapy. It is likely that the existing populations of CAR T cells generated <em>ex vivo</em> to address relapsed disease may not be able to address minimal residual disease (MRD). Therefore, we have developed a clinically appealing approach to sustaining the persistence of CAR T cells independent of TAA by providing signaling through the common gamma chain receptor (gc). Administration of exogenous soluble recombinant cytokines that signal through the gc, such as interleukin (IL)-2, have been used clinically to sustain the persistence of adoptively transferred T cells. However, systemic high-dose administration has resulted in dose-limiting toxicities. Unlike IL-2, IL-15 possesses numerous attributes desirable for adoptive therapy and has been ranked among the most valuable immunotherapeutic agent for cancer treatment. It is a pro-survival cytokine that promotes the survival of long-lived T-cell memory subsets and <em>in vivo</em> antitumor activity. Unlike other gc family cytokines, IL-15 is transpresented to responding T cells in the context of IL-15 receptor alpha (IL-15Ra). Therefore, we <em>hypothesized</em> that a membrane-bound IL-15 fusion protein (mIL15) tethered to the cell surface would enhance T-cell costimulation to support persistence independent of CAR activation by preserving T-cell memory potential and maintain antitumor activity in the presence of low TAA. Using clinically compliant methods, the generated mIL15-CAR T cells mimicked the physiologic mechanism of transpresentation to sustain costimulation via phosphorylation of signal transducer and activator of transcription (pSTAT5). In contrast to conventional CD19-specific CAR T cells, mIL15-CAR T cells persisted in mice independent of the presence of TAA and mediated potent rejection of a systemically distributed CD19⁺ leukemia. The potential for sustained immunity against B-cell malignancies was shown as, in the absence of antigen, mIL15-CAR T cells were long-lived and adopted a desirable CD45RO^negCCR7⁺ “low-differentiation” state with a memory-like molecular profile and phenotype. These results have direct implications for the design of an adoptive immunotherapy clinical trial evaluating mIL15-CAR T cells in the setting of MRD and warrants further investigation of mIL15 to engineer T cells targeting other tumor cells that have sequestered or low levels of TAA.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• Hurton, Lenka

Contributors dc:contributor

• Laurence J.N. Cooper, M.D., Ph.D.
• Joya Chandra, Ph.D.
• Gianpietro Dotti, Ph.D.

• immunotherapy
• cytokines
• IL-15
• chimeric antigen receptor
• T-cell persistence
• memory
• memory stem cell
• leukemia
• B-ALL
• Medical Biotechnology
• Medical Immunology
• Medicine and Health Sciences
• Other Immunology and Infectious Disease

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/421

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1463