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

ABSTRACT: Axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory large B-cell lymphoma (LBCL), has comparable efficacy across conventional LBCL markers. We analysed whether pre- and posttreatment tumour immune contexture determines clinical outcomes for axi cel–treated patients in the ZUMA-1 pivotal study. Longitudinal evaluation of the tumour microenvironment (TME) uncovered dynamic patterns that occurred rapidly after axi-cel (within 2 weeks) in responders—pronounced enhancement of T- and myeloid cell signatures and diminution of B cell signature. Clinical response and overall survival associated with high CD8+ T-cell density (Immunoscore) and immune gene expression (Immunosign21) in TME pretreatment, which was paralleled by blood CAR T-cell levels posttreatment. High density of regulatory T cells in TME pretreatment associated with reduced axi-cel–related neurologic toxicity. At relapse, the TME evolved toward an immune-detrimental contexture with decreased T-cell–related and increased counterregulatory immune signatures and B cell lineage antigens. A TME rich in T-cell attractive chemokines (CCL5, CCL22), gamma-chain receptor cytokines (IL-15, IL-7, IL-21), and interferon regulated molecules associated with T-cell infiltration and markers of activity, a result validated in 2 independent datasets totalling ≈300 LBCL samples. These findings advance mechanistic understanding of CAR T-cell therapy and foster biomarker development and treatment optimizations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197977 | GEO | 2022/09/23

REPOSITORIES: GEO

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Project description:A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive tumor microenvironment (TME), which is densely populated and supported by protumoral glioma-associated microglia and macrophages (GAMs). Targeting CD47, a don't-eat-me signal overexpressed by tumor cells, disrupts the CD47-SIRPalpha axis and induces GAM phagocytic function. However, antibody-mediated CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. To overcome these limitations, we combined local CAR T cell therapy with paracrine GAM modulation to effectively eliminate GBM. To this end, we engineered a new CAR T cell against epidermal growth factor receptor variant III (EGFRvIII) that constitutively secretes a signal regulatory protein gamma (SIRPgamma)-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eliminated EGFRvIII+ GBM in a dose-dependent manner in vitro and eradicated orthotopically xenografted EGFRvIII-mosaic GBM by locoregional application in vivo. This resulted in significant tumor-free long-term survival, followed by partial tumor control upon tumor re-challenge. Combining anti-CD47 antibodies with anti-EGFRvIII CAR T cells failed to achieve a similar therapeutic effect, underscoring the importance of sustained paracrine GAM modulation. Multidimensional brain immunofluorescence microscopy and in-depth spectral flow cytometry on GBM-xenografted brains showed that anti-EGFRvIII-SGRP CAR T cells accelerated GBM clearance, increased CD68+ cell trafficking to tumor scar sites and promoted GAM-mediated tumor cell uptake. In a peripheral lymphoma mouse xenograft model, anti-CD19-SGRP CAR T cells had superior efficacy to conventional anti-CD19 CAR T cells. Validation on human GBM explants revealed that anti-EGFRvIII-SGRP CAR T cells had a similar tumor-killing capacity to anti-EGFRvIII CAR monotherapy but showed a slight improvement in the maintenance of tumor-infiltrated CD14+ cells. Thus, local anti-EGFRvIII-SGRP CAR T cell therapy combines the potent antitumor effect of engineered T cells with the modulation of the surrounding innate immune TME. This results in the additive elimination of bystander EGFRvIII- tumor cells in a manner that overcomes the main mechanisms of CAR T cell therapy resistance, including tumor innate immune suppression and antigen escape.

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

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