TROP2 CAR T Cell Therapy(Dana-Farber Cancer Institute)

Due to their high heterogeneity and complex tumor microenvironment, the treatment of solid tumors by CAR-T cell technology is limited. This study developed bi-specific Trop2/PD-L1 specific third-generation CAR-T cells by lentiviral infection. The specific killing ability of the bi-specific CAR-T cells against Trop2⁺ and PD-L1⁺ expressed on the gastric cancer cell line by CCK-8 assay, was confirmed in vitro. The killing ability of bi-specific Trop2/PD-L1 CAR-T cells was higher than that of mono-specific CAR-T cells (Trop2 CAR-T and PD-L1 CAR-T) and the independent control group (CD19-CAR-T and CIK). The bi-specific Trop2/PD-L1 CAR-T cells produced IFN-γ and IL-2 in response to the overexpression of Trop2 and PD-L1 in gastric cancer cells through ELASA assay. The levels of cytokines (IFN-γ and IL-2) released by bi-specific Trop2/PD-L1 CAR-T cells were the highest among all other types of CAR-T cells and the independent control group. To further demonstrate the ability of bi-specific Trop2/PD-L1 CAR-T cells in vivo, this study testified to the anti-tumor effect of several types of CAR-T cells through a xenograft model bearing human gastric tumors. The results indicated that bi-specific Trop2/PD-L1 CAR-T cells can significantly reduce the tumor growth through intratumoral injection, with a higher inhibition effect than Trop2 specific CAR-T cells and the independent control group (CD19-CAR-T and untreated group). These results suggest that novel bi-specific Trop2/PD-L1 CAR-T cells are able to target Trop2/PD-L1 and checkpoint blockade, and reveal the killing effect on gastric cancer, therefore improving the killing effect of CAR-T cells in solid tumors.

EGFR tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes for EGFR-mutated non-small cell lung cancer (NSCLC) patients, but relapse frequently occurs due to drug tolerant persister (DTP) cells that can evolve and develop diverse mechanisms of drug resistance. In samples from patients with EGFR-mutated NSCLC treated with EGFR-TKIs in the neoadjuvant setting, we observed enriched expression of the cell surface protein TROP2, a target of clinically active antibody drug conjugates (ADCs). We confirmed these findings across multiple EGFR-mutated NSCLC cell line and patient-derived xenograft models treated with osimertinib in vivo. Treatment with the TROP2 ADC sacituzumab govitecan at the time of osimertinib-induced minimal residual disease only modestly delayed tumor recurrence in vivo, whereas a single infusion of sacituzumab-based TROP2-directed CAR-T cells significantly prolonged relapse-free survival, with evidence of cure. These data highlight the potential of engineering TROP2 CAR-T cell therapy to eliminate EGFR DTPs in patients.