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

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.

Peripheral blood cellular profile at pre-lymphodepletion is associated with CD19-targeted CAR-T cell-associated neurotoxicity

“…In addition, CXCL-9 levels were found to be highly correlated with CD45 + EVs and IL-10 plasma levels, as well as senescent CD8 + T cells. Notably, it has been reported that CXCL-9 expression in the tumor microenvironment at the pre-treatment stage affects the local immune landscape in patients treated with CAR-T cell therapy ( 17 ). Speculatively, CXCL-9 circulating levels may provide information about the role of the tumor microenvironment in the onset of ICANS ( 17 ).…”

“…Notably, CAR-T cell-induced neurotoxicity can be largely influenced by the pre-treatment tumor immune microenvironment, and by the crosstalk among lymphoma cells, myeloid cells, cytotoxic and regulatory T cells ( 17 ).…”

Managing the TME to improve the efficacy of cancer therapy

“…Semin Oncol 2017). Included in this perspective is an emerging concept of the immunoscore, which attempts to predict favorable responses based on infiltrating T-cell density ( 24 ). Unfavorable responses can also be predicted, especially when the presence of other types of immune cells (e.g.…”

CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies

“…They bind to Programmed death-1 (PD-1) expressed on activated CAR-T cells, inhibiting their function. Recent study also showed that the TME of large B cell lymphoma is the key determinant of CD19-CAR-T cell activity ( 41 ). Several strategies have been proposed to overcome the immunosuppressive effects of the TME, including the blockade of immune checkpoints, promoting CAR-T cell activity and remodeling the TME ( Figure 1 ).…”