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Co-transplantation of CAR-gene Engineered Precursor T Cells Leads To Suppressed T Cell Development and Increased NK Cell-based CAR-mediated Anti-leukemic Activity

ABSTRACT: CAR gene expression on precursor T cells (preTs) that have been generated in vitro from engineered hematopoietic stem cells may reduce the risk of leukemia relapse upon co-transplantation in an MHC-independent manner. Setting the expression of an anti-murine CD19 CAR under the control of an inducible promoter allowed time-dependent assessment of its impact on in vivo development. Adoptive transfer of engineered preTs along with T cell-depleted bone marrow resulted in potent anti-leukemia effects even in fully MHC-class I and II mismatched recipients. Anti-leukemia effects entirely relied on the in vivo development of CAR-expressing natural killer cells since NK cell depletion after transplantation resulted in a complete abrogation of anti-leukemic efficacy. Gene expression profiling revealed that enforced CAR expression on preTs led to an activated shift of transcriptional key factors to those being associated with NK cell development such as Nfil3, Id2, and Eomes. In contrast, CAR expression on preTs blocked thymic seeding completely and prevented further T cell development. The CAR-expressing NK cell progeny of transferred preTs persisted for up to 60 days post transplantation allowing for complete B-cell recovery thereafter. Taken together, we provide new functional insights for the use of CAR-engineered preTs allowing for potent anti-leukemia efficiency within a limited time window for on target/off tumor effects.

ORGANISM(S): Mus musculus

PROVIDER: GSE104512 | GEO | 2017/10/03

SECONDARY ACCESSION(S): PRJNA412882

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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Co-transplantation of CAR-gene Engineered Precursor T Cells Leads To Suppressed T Cell Development and Increased NK Cell-based CAR-mediated Anti-leukemic Activity

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