Single-Cell Dissection of Resistance to Anti-BCMA CAR-T Cell Therapy

Researchers have uncovered that both T cell-intrinsic and microenvironment factors are associated with clinical response to anti-BCMA CAR-T cells in refractory myeloma. The findings were presented at the 17^th International Myeloma Workshop.

In this study, researchers used single-cell approaches to identify mechanisms of resistance to CAR-T cells by assessing bone marrow aspirates and peripheral blood from 17 multiple myeloma (MM) patients at different time intervals, before and after anti-BCMA CAR-T infusion. The researchers enriched CAR-T cells via flow cytometry, and scRNA-seq was performed using 10x genomics 5′ technology in combination with assessment of T-cell clonality. They also sorted CD45+ CD3- CD19- subsets from paired blood samples to achieve a better understanding the bone marrow (BM) microenvironment role in resistance.  Moreover, mass cytometry was performed on the same samples with a tailored panel.

Following data analysis, the results showed that 5/17 patients achieved excellent response or better, 6/17 had progressed and 6/17 were <3 months post CAR-T infusion. T-cells from responders juxtaposed to non-responders exhibited a more restricted T-cell receptor repertoire, overexpressed stem and memory markers such as TCF7 and overexpressed exhaustion markers, which were an unexpected finding. Also, the results showed that BM microenvironment cells in patients with disease progression showed an enrichment of specific CD14+ myelo-monocytes subsets inside the BM compared to the blood. The findings revealed those cells were negative for the tumor-associated macrophage marker CD163, and overexpressed early growth response genes.

“Together, our results uncover both T cell-intrinsic and microenvironment factors associated with clinical response to anti-BCMA CAR-T cells in refractory myeloma,” the authors wrote in their abstract. “Our findings suggest that dominant CAR-T cell clones drive the anti-tumor immune response, blunted by myeloid cells in the myeloma niche. Dissection of CAR-T cell dynamics and functional states will allow for improved CAR-T generation and/or combination immune therapies.”

Ledergor G, et al. Single Cell Dissection of Resistance to Anti-BCMA CAR-T Cell Therapy. Presented at the 17^th International Myeloma Workshop; September 12-15, 2019; Boston, MA.