Eradicating Drug-tolerant Persister Cells in <i>EGFR-</i> Mutated Non–Small Cell Lung Cancer by Targeting TROP2 with CAR-T Cellular Therapy
Simon Baldacci, Elliott J. Brea, Francesco Facchinetti, Zhaorong Li, Kenneth Ngo, Soumya Malhotra, Matthew A. Booker, Michael Tolstorukov, Sachiv Chakravarti, Conor Hinchey, Navin R. Mahadevan, Filippo Lococo, Simona D’Agnelli, Letizia Gnetti, Nicoletta Campanini, Alessandro Leonetti, William W. Feng, Jon A. Tsai, Antja-Voy Hartley, Marie-Anaïs Locquet, Ludovic Fournel, Marco Alifano, Audrey Mansuet‐Lupo, Aisha Saldanha, William Haller, Lauren M. Zasadil, Magdalena Zielinska, Karen Bui, Bishma Tuladhar, Patrick H. Lizotte, Elena V. Ivanova, Lecia V. Sequist, Prafulla C. Gokhale, Cloud P. Paweletz, Eric L. Smith, Pasi A. Jänne, David A. Barbie
Abstract
EGFR tyrosine kinase inhibitors have dramatically improved outcomes for patients with EGFR-mutated non-small cell lung cancer (NSCLC), but relapse frequently occurs because of 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 tyrosine kinase inhibitors in the neoadjuvant setting, we observed enriched expression of the cell surface protein TROP2, a target of clinically active antibody-drug conjugates (ADC). 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 chimeric antigen receptor (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. SIGNIFICANCE: We provide a rationale for targeting TROP2 in EGFR-mutated NSCLC DTPs. In contrast to TROP2 ADC therapy, targeting of TROP2 with CAR-T cells can eliminate osimertinib-induced DTPs in vivo, revealing the promise of developing novel TROP2-based CAR-T cells to promote durable response and prevent disease relapse in patients.