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 toxicity, and more than half of patients relapse. As monocytes emerged as key players in CAR therapy, we sought to evaluate the evolution of HLA-DR expression on monocytes (mHLA-DR) before and after commercial anti-CD19 CAR T-cell infusion in a large cohort (n = 103) of patients with R/R LBCL and its association with adverse events and treatment response. Cy-Flu-based lymphodepletion (LD) upregulated mHLA-DR in 79% of the cases, whereas in 2l% of cases (15 patients), the mHLA-DR level decreased after LD, and this decrease was associated with poorer outcome. Low mHLA-DR at day minus 7 (D-7) (<13 500 antibodies per cell) before CAR T-cell infusion correlated with older age, 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 than the higher mHLA-DR D-7 group. For toxicity management, tocilizumab was more frequently used in the low-mHLA-DR D-7 group. These data suggest that monocyte dysregulation before 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 for improving CAR therapy.

• Authors: Estelle Bourbon, Pierre Sesques, Morgane Gossez, Jérémie Tordo, Emmanuelle Ferrant, Violaine Safar, Florent Wallet, Guillaume Aussedat, Alizée Maarek, Fadhela Bouafia, Lionel Karlin, Dana Ghergus, Camille Golfier, Hélène Lequeu, Anne Lazareth, Vérane Schwiertz, Sébastien Viel, Maryam Idlhaj, Hervé Ghesquières, Guillaume Monneret, Emmanuel Bachy, Fabienne Venet
• Journal: Blood advances (Blood Adv) Vol. 7 Issue 5 Pg. 744-755 (03 14 2023) ISSN: 2473-9537 [Electronic] United States
• PMID: 35439292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• HLA-DR Antigens

Topics

• Humans
• Monocytes
• Immunotherapy, Adoptive (adverse effects)
• Neoplasm Recurrence, Local
• HLA-DR Antigens
• Lymphoma, Large B-Cell, Diffuse (therapy)