Journal
CLINICAL CANCER RESEARCH
Volume 24, Issue 16, Pages 3981-3993Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-1788
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Funding
- Forschungskredit University of Zurich [54171101]
- Swiss Cancer League [KFS-3115-02-2013, KFS-4231-08-2017]
- Hoch spezialisierte Medizin of the Canton Zurich
- Swiss Tumor Immunology Institute
- Zurich Cancer League
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Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Delta-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Delta-CD28 CAR was tested clinically in a patient with MPM. Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the Delta-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Delta-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Delta-CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP-Delta-CD28/CD3 zeta CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. (C) 2018 AACR.
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