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Targeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models [scRNA-seq]

ABSTRACT: We exploited a lentiviral vector-based platform to engineer hematopoietic stem cells ex vivo with the aim of releasing, via their tumor-infiltrating monocyte/macrophage progeny, IFN-a or IL-12 at the tumor site in a spatial and temporal regulated manner. Taking advantage of a syngeneic GBM mouse model, we showed that inducible release of IFN-a within the TME achieved robust tumor inhibition up to eradication and outperformed systemic treatment with the recombinant protein in terms of efficacy, tolerability and specificity. Single-cell RNAseq of the tumor immune infiltrate revealed reprogramming of the immune microenvironment towards a pro-inflammatory and anti-tumoral state associated with loss of a macrophage subpopulation predicting poor prognosis in human GBM.

ORGANISM(S): Mus musculus

PROVIDER: GSE173645 | GEO | 2022/06/01

REPOSITORIES: GEO

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Project description:Treatment efficacy with chimeric antigen receptor (CAR) T cell therapy in glioblastoma (GBM) is undermined by an immunosuppressive tumor microenvironment (TME). We previously showed that CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces anti-tumor activity against recurrent GBM and causes upregulation of programmed death-ligand 1 (PD-L1) in the TME. Here, we conducted a phase I trial to study the safety and tolerability of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients with newly diagnosed, EGFRvIII+ GBM (n=7). Treatment was well tolerated in this small cohort without incidence of dose-limiting toxicity. However, no signal of efficacy was detected with a median progression-free survival of 5.2 months (90% CI, 2.9 – 6.0 months) and overall survival of 11.8 months (90 % CI, 9.2 – 14.2 months). We aimed to elucidate reasons for limited efficacy through correlative analyses. Using BBZ qPCR, we found circulating CAR T cells in 5 out of 7 patients at the time of repeat resection, but only in 1 patient in the tumor. However, shared T-cell receptors (TCRs) were found between the infusion product and the relapsed tumors, which could indicate an infiltration but lack of persistence of the CAR T cells. We further compared the tumor microenvironment of the tumors harvested before and after CAR+aPD1 administration using single cell RNA sequencing and observed comparable proportions of the major immune cell subsets. However, the myeloid and T cells infiltrating the tumors significantly evolved, with more exhausted, regulatory, and IFN-stimulated T cells at the relapse. At that time, the amount of IFN-stimulated T cells positively correlated with time from relapse to death. Together, these findings suggest that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicate a need to consider alternative immunotherapeutic strategies. ClinicalTrials.gov registration: NCT03726515.

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Targeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models [scRNA-seq]

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