Antagonism of IAPs Enhances CAR T-cell Efficacy
| Autor: | Kelly M Ramsbottom, Ilia Voskoboinik, Najoua Lalaoui, Conor J. Kearney, Paul A. Beavis, Jane Oliaro, Ricky W. Johnstone, Andrew J. Freeman, Robert G. Ramsay, Emily J. Lelliott, Jessica Michie, John Silke, Vignesh Narasimhan, Phillip K. Darcy, Stephin J. Vervoort |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment T cell T-Lymphocytes Immunology Receptors Antigen T-Cell Apoptosis Inhibitor of apoptosis Immunotherapy Adoptive Inhibitor of Apoptosis Proteins 03 medical and health sciences Mice 0302 clinical medicine Antigen Cell Line Tumor Neoplasms medicine Cytotoxic T cell Animals Humans Receptors Chimeric Antigen business.industry Immunotherapy Chimeric antigen receptor Disease Models Animal 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Cytokines Tumor necrosis factor alpha business |
| Zdroj: | Cancer immunology research. 7(2) |
| ISSN: | 2326-6074 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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