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RNA sequencing of blood-brain barrier (BBB) microvessels from mice with orthotopic GBM showing the benefit of triple therapy combining anti-immune checkpoint therapy with dual-anti angiogenic therapy.

ABSTRACT: Glioblastoma multiforme (GBM) is a non T cell-inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T cell cytotoxicity. The alleviation of immunosuppression might be a prerequisite for succesful immune checkpoint therapy in GBM. We here combine anti-angiogenic and immune checkpoint therapy and demonstrate improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of vascular endothelial growth factor (VEGF), Angiopoietin-2 (Ang-2) and programmed cell death protein-1 (PD-1) significantly extended survival compared to vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of cytotoxic T-lymphocytes that inversely correlated with myeloid-derived suppressor and regulatory T cells. Furthermore, transcriptomic analysis of GBM microvessels indicates a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce anti-tumor immunity through a normalized vasculature.

ORGANISM(S): Mus musculus

PROVIDER: GSE130324 | GEO | 2021/03/01

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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RNA sequencing of blood-brain barrier (BBB) microvessels from mice with orthotopic GBM showing the benefit of triple therapy combining anti-immune checkpoint therapy with dual-anti angiogenic therapy.

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