Antagonism of IAPs enhances CAR T-cell efficacy Academic Article uri icon

abstract

  • Chimeric antigen receptor (CAR) T-cell therapy has proven successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B-cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrated that antagonizing the "inhibitor of apoptosis proteins" with the clinical smac-mimetic, birinapant, significantly enhanced the antitumor activity of CAR T cells in a tumor necrosis factor (TNF)-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T-cell-derived TNF. Combining CAR T-cell therapy with birinapant significantly reduced established tumor growth in vivo, where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrated the synergistic potential of combining CAR T-cell therapy with smac-mimetics. Taken together, we identified CAR T-cell-derived TNF as a potent antitumor effector, which can be further harnessed by smac-mimetics.

authors

  • Michie, J
  • Beavis, PA
  • Freeman, AJ
  • Vervoort, SJ
  • Ramsbottom, KM
  • Narasimhan, V
  • Lelliott, EJ
  • Lalaoui, N
  • Ramsay, RG
  • Johnstone, RW
  • Silke, J
  • Darcy, PK
  • Voskoboinik, I
  • Kearney, CJ
  • Oliaro, J

publication date

  • February 1, 2019