Journal
MOLECULAR THERAPY
Volume 26, Issue 4, Pages 963-975Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2018.01.020
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Funding
- NHLBI [HL125018]
- NIAID [AI124769, AI129594, AI130197]
- Houston Methodist Career Cornerstone Award from the National Institute of Allergy and Infectious Diseases
- Houston Methodist Research Institute for Academic Medicine NIH Competitiveness Initiative Award from the National Institute of Allergy and Infectious Diseases
- Baylor-UT Houston Center for AIDS Research Core Support Grant from the National Institute of Allergy and Infectious Diseases [AI036211]
- Caroline Wiess Law Fund for Research in Molecular Medicine
- Texas Children's Hospital Pediatric Pilot Research Fund
- Lymphoma SPORE Developmental Research Program from Baylor College of Medicine [P50 CA126752]
- Methodist Research Institute [P50 CA126752]
- Celgene research funding
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Chimeric antigen receptor (CAR)-modified T cell therapy has the potential to improve the overall survival of patients with malignancies by enhancing the effectiveness of CAR T cells. Precisely predicting the effectiveness of various CAR T cells represents one of today's key unsolved problems in immunotherapy. Here, we predict the effectiveness of CAR-modified cells by evaluating the quality of the CAR-mediated immunological synapse (IS) by quantitation of F-actin, clustering of tumor antigen, polarization of lytic granules (LGs), and distribution of key signaling molecules within the IS. Long-term killing capability, but not secretion of conventional cytokines or standard 4-hr cytotoxicity, correlates positively with the quality of the IS in two different CAR T cells that share identical antigen specificity. Xenograft model data confirm that the quality of the IS in vitro correlates positively with performance of CAR-modified immune cells in vivo. Therefore, we propose that the quality of the IS predicts the effectiveness of CAR-modified immune cells, which provides a novel strategy to guide CAR therapy.
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