Haradhvala et al. performed scRNAseq on 105 samples from 32 patients with large B-cell lymphoma treated with either axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) to identify the drivers of clinical response. In tisa-cel treated patients, expansion of proliferative memory-like CD8+ T cell clones was associated with response, whereas responders in axi-cel treated patients displayed heterogeneous populations. Increased frequencies of CAR T regulatory cells (CAR-Treg) were found in non-responders to axi-cel infusions. CAR-Treg cells making up 5% of total infused CAR T cells was sufficient to drive late tumor relapses and suppress conventional CAR T cell expansion.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA. Cancer Program, The Broad Institute, Cambridge, MA, USA. (2) Cancer Center, Massachusetts Genera
Author Info: (1) Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA. Cancer Program, The Broad Institute, Cambridge, MA, USA. (2) Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (3) Cancer Program, The Broad Institute, Cambridge, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Cancer Program, The Broad Institute, Cambridge, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Haematology, University College London Hospitals, London, UK. (5) Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (6) Cancer Program, The Broad Institute, Cambridge, MA, USA. Program in Computational Biology and Quantitative Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (7) Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (8) Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (9) Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Cancer Program, The Broad Institute, Cambridge, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (12) Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (13) Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (14) Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (15) IBM Research, New York, NY, USA. (16) IBM Research, New York, NY, USA. (17) IBM Research, New York, NY, USA. (18) Cancer Program, The Broad Institute, Cambridge, MA, USA. (19) Cancer Program, The Broad Institute, Cambridge, MA, USA. (20) Cancer Program, The Broad Institute, Cambridge, MA, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (22) IBM Research, New York, NY, USA. (23) Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (25) Cancer Program, The Broad Institute, Cambridge, MA, USA. cwu@partners.org. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. cwu@partners.org. (26) Cancer Program, The Broad Institute, Cambridge, MA, USA. gadgetz@broadinstitute.org. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. gadgetz@broadinstitute.org. Harvard Medical School, Boston, MA, USA. gadgetz@broadinstitute.org. (27) Cancer Program, The Broad Institute, Cambridge, MA, USA. mvmaus@mgh.harvard.edu. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. mvmaus@mgh.harvard.edu. Harvard Medical School, Boston, MA, USA. mvmaus@mgh.harvard.edu.
