Distinct cellular dynamics following CD19 and CD7 CAR-T therapies revealed by high-dimensional CyTOF analysis and impact on clinical outcomes
Zhipeng Zhou, Yiyang Ding, Zhuojun Liu, Zhifan Zhao, Ting Zhao, Xiaohui Zhang, Xiaojun Huang, Meng Lyu, Xuying Pei, Xiangyu ZhaoAbstract
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.