Baseline immune state and T-cell clonal kinetics are associated with durable response to CAR-T therapy in large B-cell lymphoma

Blood. 2024 Dec 12;144(24):2490-2502. doi: 10.1182/blood.2024024381.

Abstract

Engineered cellular therapy with CD19-targeting chimeric antigen receptor T cells (CAR-Ts) has revolutionized outcomes for patients with relapsed/refractory large B-cell lymphoma (LBCL), but the cellular and molecular features associated with response remain largely unresolved. We analyzed serial peripheral blood samples ranging from the day of apheresis (day -28/baseline) to 28 days after CAR-T infusion from 50 patients with LBCL treated with axicabtagene ciloleucel by integrating single-cell RNA and T-cell receptor sequencing, flow cytometry, and mass cytometry to characterize features associated with response to CAR-T. Pretreatment patient characteristics associated with response included the presence of B cells and increased absolute lymphocyte count to absolute monocyte count ratio (ALC/AMC). Infusion products from responders were enriched for clonally expanded, highly activated CD8+ T cells. We expanded these observations to 99 patients from the ZUMA-1 cohort and identified a subset of patients with elevated baseline B cells, 80% of whom were complete responders. We integrated B-cell proportion ≥0.5% and ALC/AMC ≥1.2 into a 2-factor predictive model and applied this model to the ZUMA-1 cohort. Estimated progression-free survival at 1 year in patients meeting 1 or both criteria was 65% vs 31% for patients meeting neither criterion. Our results suggest that patients' immunologic state at baseline affects the likelihood of response to CAR-T through both modulation of the T-cell apheresis product composition and promoting a more favorable circulating immune compartment before therapy. These baseline immunologic features, measured readily in the clinical setting before CAR-T, can be applied to predict response to therapy.

MeSH terms

  • Adult
  • Aged
  • Antigens, CD19 / immunology
  • Biological Products / therapeutic use
  • Female
  • Humans
  • Immunotherapy, Adoptive* / methods
  • Lymphoma, Large B-Cell, Diffuse* / immunology
  • Lymphoma, Large B-Cell, Diffuse* / therapy
  • Male
  • Middle Aged
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Chimeric Antigen / immunology
  • T-Lymphocytes / immunology
  • Treatment Outcome

Substances

  • axicabtagene ciloleucel
  • Receptors, Chimeric Antigen
  • Biological Products
  • Antigens, CD19
  • Receptors, Antigen, T-Cell