HLA-DR expression on monocytes and outcome of anti-CD19 CAR-T cell therapy for large B-cell lymphoma.

Despite their unprecedented success in relapsed/refractory (R/R) large B-cell lymphoma (LBCL), anti-CD19 CAR-T cells are associated with significant toxicities, and more than half of the patients will relapse. As monocytes emerged as key players in CAR therapy, we sought to evaluate the evolution of HLA-DR expression on monocytes (mHLA-DR) prior to and following commercial anti-CD19 CAR-T cell infusion in a large cohort of 103 patients with R/R LBCL, and its association with adverse events and treatment response. Cyclophosphamide/fludarabine-based lymphodepletion (LD) upregulated mHLA-DR in 79% of the cases, while 15 patients (21%) decreased mHLA-DR level following LD, which was associated with poorer outcome. Low mHLA-DR at day-7 (D-7) (< 13 500 antibody binding per cell, AB/C) before CAR-T cell infusion correlated with older ager, poorer performance status, higher tumor burden and elevated inflammatory markers. With a median follow-up of 7.4 months, patients with low mHLA-DR D-7 exhibited a poorer duration of response and survival compared with the higher group. For toxicity management, tocilizumab was more frequently used in the low mHLA-DR D-7 group. These data suggest that monocyte dysregulation prior to LD, characterized by the downregulation of mHLA-DR, correlates with an inflammatory and immunosuppressive tumor environment, and is associated with failure of anti-CD19 CAR-T cells in patients with R/R LBCL. Modulation of these myeloid cells represents a promising field to improve CAR therapy.