2. Academic Validation
  3. The IAP antagonist birinapant enhances chimeric antigen receptor T cell therapy for glioblastoma by overcoming antigen heterogeneity

The IAP antagonist birinapant enhances chimeric antigen receptor T cell therapy for glioblastoma by overcoming antigen heterogeneity

  • Mol Ther Oncolytics. 2022 Nov 15;27:288-304. doi: 10.1016/j.omto.2022.11.004.
Edward Z Song 1 2 3,  Xin Wang 3 4,  Benjamin I Philipson 1 2,  Qian Zhang 1 2,  Radhika Thokala 1 2 3,  Logan Zhang 2 3 5,  Charles-Antoine Assenmacher 6,  Zev A Binder 2 3 5,  Guo-Li Ming 3 4 7 8 9,  Donald M O'Rourke 2 3 5,  Hongjun Song 3 4 7 8 10,  Michael C Milone 1 2 3
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, PCAM SPE 8-101, Philadelphia, PA 19104, USA.
  • 2 Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, PCAM SPE 8-101, Philadelphia, PA 19104, USA.
  • 3 Glioblastoma Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, PCAM SPE 8-101, Philadelphia, PA 19104, USA.
  • 4 Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6 Comparative Pathology Core, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7 Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 9 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 10 The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
PMID: 36458202 DOI: 10.1016/j.omto.2022.11.004
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 novel and feasible approach to overcoming tumor antigen heterogeneity and enhancing CAR T cell therapy for GBM.

Keywords

CAR T cell; IAP antagonist; antigen heterogeneity; birinapant; glioblastoma.

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