Eradicating Drug Tolerant Persister Cells in EGFR-Mutated Non-Small Cell Lung Cancer by Targeting TROP2 with CAR-T cellular therapy

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 an EGFR-TKIs in the neoadjuvant setting, we observed uniformly elevated expression of the cell surface protein TROP2, a target of clinically active antibody drug conjugates (ADCs). We further confirmed that TROP2 expression is enriched in DTPs following osimertinib treatment of EGFR-mutated NSCLC cell lines and xenograft models. At the time of osimertinib-induced minimal residual disease, treatment with TROP2 ADC sacituzumab govitecan had only a modest impact on delaying tumor recurrence in vivo. In contrast, a single treatment of TROP2 directed CAR-T treatment significantly prolonged relapse-free survival with evidence of cure, highlighting the ability of CAR-T therapy to eliminate DTPs in vivo. scRNA-Seq samples of residual tumor tissues and lymph nodes from patients after treatment