Aberrant Lck signal via CD28 co-stimulation augments antigen-specific functionality and tumor control by redirected T cells with PD-1 blockade in humanized mice

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 co-stimulatory domains including CD28, -CD28 (lacking lck binding moiety) or 4-1BB were established. CAR-T cells were characterized in vitroand anti-tumor efficacy was tested in vivoin a humanized mouse model in combination with PD-1 blockade. Finally, the -CD28 CAR was tested clinically in a MPM patient. Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the -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 -CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a MPM patient, the -CD28 CAR could be detected for up to 21 days and showed functionality. Conclusions: Overall, anti-FAP--CD28/CD3 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 MPM patient. Therefore, further clinical investigation of this optimized CAR is warranted.

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