Distinct cellular dynamics following CD19 and CD7 CAR-T therapies revealed by high-dimensional CyTOF analysis and impact on clinical outcomes
TL;DR
Compared with CD19 CAR-T therapy, CD7 CAR-T therapy was characterized by reduced CD8+ CAR-T persistence, early exhaustion, and delayed immune reconstitution, correlating with increased infections and higher non-relapse mortality.
Abstract
Abstract Background and Objectives CD7 and CD19 chimeric antigen receptor T-cell (CAR-T) therapies induce high remission in T-cell acute lymphoblastic leukemia; however, clinical outcomes of CD7 CAR-T therapy are less favorable compared with those of CD19 CAR-T therapy due to profound immune dysfunction, elevated infection, and non-relapse mortality (NRM). Whether these differences arise from distinct immune remodeling patterns that shape CAR-T cell persistence, functional fitness, and host immune recovery, remains unknown. Methods We analyzed 74 patients (52 CD19; 22 CD7) who received CAR-T therapy. A subset of 28 patients underwent prospective immune monitoring with 107 longitudinal samples profiled using 40-marker cytometry by time-of-flight to assess CAR-T cell kinetics, exhaustion, host immune remodeling, and clinical associations. Results High-dimensional profiling revealed strikingly divergent immune trajectories of CD19 and CD7 CAR-T therapies. At day 28, CD7 CAR-T recipients exhibited diminished CD8+ CAR-T cell frequencies, early CAR-T cell exhaustion, and poor immune reconstitution, features more frequent among patients experiencing NRM. In contrast, CD19 CAR-T recipients showed sustained activation, low exhaustion, and prolonged persistence. These immunologic disparities translated into clinically meaningful differences where day-28 responses remained comparable (88.5% vs. 90.9%); however, CD7 CAR-T recipients developed higher late hematotoxicity and fatal infections, resulting in greater 1-year NRM (32.4% vs. 9.2%) and inferior overall survival (44.6% vs. 78.8%). Conclusion CD7 and CD19 CAR-T therapies are associated with distinct patterns of immune remodeling and clinical outcomes. Compared with CD19 CAR-T therapy, CD7 CAR-T therapy was characterized by reduced CD8+ CAR-T persistence, early exhaustion, and delayed immune reconstitution, correlating with increased infections and higher non-relapse mortality.