Rational design of chimeric antigen receptor T cells against glypican 3 decouples toxicity from therapeutic efficacy
| Autor: | Maria Letizia Giardino Torchia, Ryan Gilbreth, Ashley Merlino, Erin Sult, Noel Monks, Jon Chesebrough, Ravinder Tammali, Nina Chu, Jessica Tong, John Meekin, Kevin Schifferli, Kapil Vashisht, Karma DaCosta, Lori Clarke, Christina Gesse, Xiao-Tao Yao, Courtney Bridges, Gordon Moody |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Transplantation Receptors Chimeric Antigen T-Lymphocytes Immunology Receptors Antigen T-Cell Cell Biology Immunotherapy Adoptive Xenograft Model Antitumor Assays Mice Oncology Glypicans Cell Line Tumor Immunology and Allergy Animals Tumor Necrosis Factor Inhibitors Genetics (clinical) |
| Zdroj: | Cytotherapy. 24(7) |
| ISSN: | 1477-2566 |
| Popis: | Chimeric antigen receptor (CAR) T cell therapy has yielded impressive clinical results in hematological malignancies and is a promising approach for solid tumor treatment. However, toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, is a concern hampering its broader use.In selecting a lead CAR-T candidate against the oncofetal antigen glypican 3 (GPC3), we compared CARs bearing a low- and high-affinity single-chain variable fragment (scFv) binding to a similar epitope and cross-reactive with murine GPC3.Where the high-affinity CAR-T cells were toxic in vivo, the low-affinity CAR maintained cytotoxic function against antigen-positive tumor cells but did not show toxicity against normal tissues. High-affinity CAR-induced toxicity was caused by on-target, off-tumor binding, based on the observation that higher doses of the high-affinity CAR-T caused toxicity in non-tumor-bearing mice and accumulated in organs with low expression of GPC3. To explore another layer of controlling CAR-T toxicity, we developed a means to target and eliminate CAR-T cells using anti-TNF-α antibody therapy after CAR-T infusion. The antibody was shown to function by eliminating early antigen-activated, but not all, CAR-T cells, allowing a margin where the toxic response could be effectively decoupled from antitumor efficacy with only a minor loss in tumor control. By exploring additional traits of the CAR-T cells after activation, we identified a mechanism whereby we could use approved therapeutics and apply them as an exogenous kill switch that eliminated early activated CAR-T following antigen engagement in vivo.By combining the reduced-affinity CAR with this exogenous control mechanism, we provide evidence that we can modulate and control CAR-mediated toxicity. |
| Databáze: | OpenAIRE |
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