Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma

Nat Med. 2022 Sep;28(9):1872-1882. doi: 10.1038/s41591-022-01916-x. Epub 2022 Aug 29.

Abstract

Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), γ-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel-related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD19
  • Biological Products*
  • Cell Count
  • Humans
  • Immunotherapy, Adoptive / adverse effects
  • Interferons / therapeutic use
  • Interleukin-15
  • Interleukin-7 / therapeutic use
  • Lymphoma, Large B-Cell, Diffuse* / therapy
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / therapeutic use
  • Tumor Microenvironment

Substances

  • Antigens, CD19
  • Biological Products
  • Interleukin-15
  • Interleukin-7
  • Receptors, Chimeric Antigen
  • Interferons