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

Abstract

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.

The effect of immune cell traits on efficacy and adverse drug reactions of platinum drugs： A Mendelian randomization analysis

“…Bourbon E et al found that the change of HLA-DR expression on monocytes (mHLA-DR) before and after infusion of anti-CD79 CAR T cells in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) was related to adverse events and therapeutic effect. The level of mHLA-DR decreased after lymphocyte depletion, which was related to poor results (Bourbon et al 2023). Monocyte disorder before lymphocyte depletion is characterized by downregulation of mHLA-DR, which is related to in ammation and immunosuppression of tumor environment, and to the failure of anti-CD19 CAR T cells in patients with recurrent/refractory large B-cell lymphoma.…”

Early predictive factors of failure in autologous CAR T-cell manufacturing and/or efficacy in hematologic malignancies

“… 14 In BCL, CAR T-cell failure was correlated with tumor volume, extranodal sites ≥2, and a decreased expression of HLA-DR on monocytes. 5 , 15 …”