Summary

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain new insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pretreatment and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with large B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells among nonresponders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-T regulatory cells to drive relapse.

Overall design

Single-cell RNA sequencing of PBMCs and infusion products from 32 patients treated with CD19 CAR-T therapy. NOTE FROM SUBMITTER: Raw sequencing data will be available at controlled access, dbGAP.

Contributors

Nicholas J. Haradhvala†, Mark B. Leick†, Katie Maurer†, Satyen H. Gohil†, Catherine J. Wu✉️, Gad Getz✉️, Marcela V. Maus✉️

Contact

cwu@partners.org (Catherine J. Wu), gadgetz@broadinstitute.org (Gad Getz), mvmaus@mgh.harvard.edu (Marcela V. Maus)