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

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.

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Publication Details

Journal
Blood
Published
2024-09-06
DOI
https://doi.org/10.1182/blood.2024024381
Citations
15
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
4.24

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

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

Shuqiang Li, Donna Neuberg, Michela Ansuinelli, Jerome Ritz, Brodie Miles, Robert Allyn Redd, Mike Mattie, Roch Houot, Caron Alyce Jacobson, Isabella N. Grabski, Justin A. Budka, Catherine J. Wu, Katie Maurer, Yohei Arihara, Philippe A. Armand, Rafael A. Irizarry, Kenneth J. Livak, Heather A. Jacene, Haoxiang Lyu, Wesley S. Lu, Shogo Miura, Satyen H. Gohil, Carol Reynolds, Mikaela M. McDonough
article en
15 citations

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.

BloodVol. 144(24)
Broad Institute (US), University College London Hospitals NHS Foundation Trust (GB), Harvard University (US), Inserm (FR), Harvard University Press (US), Université Rennes 2 (FR), Cancer Research And Biostatistics (US), Dana-Farber Cancer Institute (US), Kite (United States) (US), Centre Hospitalier Universitaire de Rennes (FR), University College London (GB), Université de Rennes (FR), Massachusetts Institute of Technology (US)
National Science Foundation, Leukemia and Lymphoma Society, Gilead Sciences, American Society of Clinical Oncology, Dana-Farber Cancer Institute, National Institutes of Health, National Cancer Institute
Responsible consumption and production
Openalex Percentile: Top 4%
CAR-T cell therapy research
4.24
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