Post-infusion CAR T-Reg cells identify patients resistant to CD19-CAR therapy

Post-infusion CAR T-Reg cells identify patients resistant to CD19-CAR therapy NATURE MEDICINE Good, Z., Spiegel, J. Y., Sahaf, B., Malipatlolla, M. B., Ehlinger, Z. J., Kurra, S., Desai, M. H., Reynolds, W. D., Lin, A., Vandris, P., Wu, F., Prabhu, S., Hamilton, M. P., Tamaresis, J. S., Hanson, P. J., Patel, S., Feldman, S. A., Frank, M. J., Baird, J. H., Muffly, L., Claire, G. K., Craig, J., Kong, K. A., Wagh, D., Coller, J., Bendall, S. C., Tibshirani, R. J., Plevritis, S. K., Miklos, D. B., Mackall, C. L. 2022

Abstract

Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and neurotoxicity remains a challenge. Biomarkers associated with resistance and toxicity are limited. In this study, single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4+Helios+ CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity. Deep profiling demonstrated that this population is non-clonal and manifests hallmark features of T regulatory (TReg) cells. Validation cohort analysis upheld the link between higher CAR TReg cells with clinical progression and less severe neurotoxicity. A model combining expansion of this subset with lactate dehydrogenase levels, as a surrogate for tumor burden, was superior for predicting durable clinical response compared to models relying on each feature alone. These data credential CAR TReg cell expansion as a novel biomarker of response and toxicity after CAR T cell therapy and raise the prospect that this subset may regulate CAR T cell responses in humans.

View details for DOI 10.1038/s41591-022-01960-7

View details for Web of Science ID 000852940800007

View details for PubMedID 36097223