Distinct cellular dynamics associated with response to CAR-T therapy for refractory B-cell lymphoma

Haradhvala NJ*, Leick MB*, Maurer K*, Gohil SH*, Larson RC, Yao N, Gallagher KME, Katsis K, Frigault MJ, Southard J, Li S, Kann MC, Silva H, Jan M, Rhrissorrakrai K, Utro F, Levovitz C, Jacobs RA, Slowik K, Danysh BP, Livak KJ, Parida L, Ferry J, Jacobson C, Wu CJ#, Getz G#, Maus MV#
Nature Medicine (2022)


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.

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