Antagonism of IAPs enhances CAR T-cell efficacy
- 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 Year 2019-02, Volume 7, Issue #2, Page 183-192
- Journal Title
- Cancer Immunol Research
- Publication Type
- Journal Article
- 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.
- WEHI Research Division(s)
- PubMed ID
- Publisher's Version
- Rights Notice
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Creation Date: 2019-03-13 08:04:18Last Modified: 2019-03-13 09:18:54