COMBINING IAP ANTAGONISTS WITH CAR T CELL THERAPY TO TREAT GLIOBLASTOMA: THE IAP ANTAGONIST BIRINAPANT ENHANCES CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY FOR GLIOBLASTOMA BY OVERCOMING ANTIGEN HETEROGENEITY

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Cell and Molecular Biology
Discipline
Immunology and Infectious Disease
Medical Sciences
Biology
Subject
Antigen Heterogeneity
Birinapant
CAR T Cell
Glioblastoma
IAP Antagonist
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Copyright date
2022
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Author
Song, Edward, Zeyuan
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Abstract

Antigen heterogeneity that results in tumor antigenic escape is one of the major obstacles to successful chimeric antigen receptor (CAR) T cell therapies in solid tumors including glioblastoma multiforme (GBM). To address this issue and improve the efficacy of CAR T cell therapy for GBM, we developed an approach that combines CAR T cells with inhibitor of apoptosis protein (IAP) antagonists, a new class of small molecules that mediate the degradation of IAPs, to treat GBM. Here, we demonstrated that the IAP antagonist birinapant could sensitize GBM cell lines and patient-derived primary GBM organoids to apoptosis induced by CAR T cell-derived cytokines, such as tumor necrosis factor. Therefore, birinapant could enhance CAR T cell-mediated bystander death of antigen-negative GBM cells, thus preventing tumor antigenic escape in antigen-heterogeneous tumor models in vitro and in vivo. In addition, birinapant could promote the activation of NF-κB signaling pathways in antigen-stimulated CAR T cells, and with a birinapant-resistant tumor model, we showed that birinapant had no deleterious effect on CAR T cell functions in vitro and in vivo. Overall, we demonstrated the potential of combining the IAP antagonist birinapant with CAR T cells as a promising approach to overcoming tumor antigen heterogeneity and enhancing CAR T cell therapy for GBM.

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Milone, Michael, C.
Date of degree
2022
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