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BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma

ABSTRACT: Glioblastoma (GBM) is the deadliest brain malignancy without effective treatments. Here, we report that epidermal growth factor receptor-targeted chimeric antigen receptor T cells (EGFR CAR-T) are effective in suppressing the growth of GBM cells in vitro and xenografts derived from GBM cell lines and patients in mice. However, mice soon acquire resistance to EGFR CAR-T cell treatment, limiting its potential use in the clinic. To find ways to improve the efficacy of EGFR CAR-T cells, we performed genomics and transcriptomics analysis for GBM cells incubated with EGFR CAR-T cells, and found that a large cohort of genes including immunosuppressive genes as well as enhancers in vicinity are activated. BRD4, an epigenetic modulator functioning on both promoter and enhancer, is required for the activation of these immunosuppressive genes. Accordingly, inhibition of BRD4 by JQ1 blocks the activation of these immunosuppressive genes. Combination therapy with EGFR CAR-T cells and JQ1 suppresses the growth and metastasis of GBM cells, and prolonged survival in mice. We demonstrate that transcriptional modulation by targeting epigenetic regulators could improve the efficacy of immunotherapy including CAR-T, providing a therapeutic avenue for treating GBM in the clinic.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174617 | GEO | 2021/05/20

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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BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma

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