PD1+TIGIT+2B4+KLRG1+ cells might underlie T-cell dysfunction in patients treated with BCMA-directed CAR-T therapy

Abstract Chimeric antigen receptor (CAR-T) cell therapy has shown rapid, frequent and deep responses in patients with relapsed, refractory multiple myeloma (RRMM). However, relapse following CAR-T is frequently observed and the cause for resistance is not well defined. Among the potential mechanism of resistance, T cell intrinsic factors may be an important source of failure. Here, we used spectral flow cytometry to identify the change in T cell phenotypes in bone marrow aspirates at different stages of multiple myeloma progression, including cases that relapsed after anti-BCMA CAR-T therapies. We identified completely different T cell phenotypes in RRMM and post CAR-T relapse cases compared to healthy donors and earlier stages of multiple myeloma, a novel double negative CD3+ T cells in RRMM and CAR-T relapsed cases, and difference in CD8 T cell phenotype at the baseline between peripheral blood and bone marrow from healthy donors. We found that the majority of T cells in RRMM, and significant subset of T cells in post CAR-T relapsed cases, expressed multiple co-inhibitory markers including PD1, TIGIT, 2B4 and KLRG1.