Timing of anti-PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma.

Abstract

ABSTRACT:

More than half of the patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be partly due to PD-1/PD-L1-associated CAR T-cell dysfunction. We report data from a phase 1 clinical trial (NCT02706405), in which adults with LBCL were treated with autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR T-cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell-associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome and inferior efficacy, which was associated with slower accumulation of CAR T cells and lower concentrations of inflammatory cytokines in the blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR T-cell accumulation in the blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR T-cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR T-cell kinetics early after infusion, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR T cells in the blood, late regression of CD19+ and CD19- tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR T-cell immunotherapy for adults with LBCL.

• Authors: Alexandre V Hirayama, Erik L Kimble, Jocelyn H Wright, Salvatore Fiorenza, Jordan Gauthier, Jenna M Voutsinas, Qian Wu, Cecilia C S Yeung, Nicolas Gazeau, Barbara S Pender, Delaney R Kirchmeier, Aiko Torkelson, Abigail N Chutnik, Ryan D Cassaday, Aude G Chapuis, Damian J Green, Hans-Peter Kiem, Filippo Milano, Mazyar Shadman, Brian G Till, Stanley R Riddell, David G Maloney, Cameron J Turtle
• Journal: Blood advances (Blood Adv) Vol. 8 Issue 2 Pg. 453-467 (01 23 2024) ISSN: 2473-9537 [Electronic] United States
• PMID: 37903325 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: © 2024 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

• B7-H1 Antigen

Topics

• Adult
• Humans
• B7-H1 Antigen
• Cytokine Release Syndrome (etiology)
• Immunotherapy
• Immunotherapy, Adoptive (adverse effects, methods)
• Lymphoma, Large B-Cell, Diffuse (therapy, etiology)