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Anti-seed PNAs targeting multiple oncomiRs for brain tumor therapy

ABSTRACT: Glioblastoma (GBM) is one of the most lethal malignancies in the United States with poor survival and high recurrence rates, suggesting the need for approaches targeting the most important molecular drivers of tumor growth. Here, we aimed to simultaneously target oncomiRs 10b and 21, which have been reported to drive the aggressive growth and invasiveness of GBM. We designed short (8-mer bases) gamma-(g)-modified peptide nucleic acids (sPNAs), which target the seed region of oncomiRs 10b and 21 with high affinity. We entrapped these anti-miR sgPNAs in nanoparticles (NPs) formed from a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG). The surfaces of the NPs were functionalized with aldehydes to produce bioadhesive NPs: we have previously shown that these bioadhesive NPs (BNPs) produce superior transfection efficiency, with a tropism for tumor cells. The sgPNA BNPs showed superior anti-miR efficacy in comparison to the regular full length PNA BNPs in vitro. When combined with temozolomide, sgPNABNPs administered via convection-enhanced delivery (CED) inhibited the growth of intracranial tumors and significantly improved the survival of animals (>120 days). RNA sequencing analysis revealed the downregulation of multiple genes associated with PI3-Akt, focal adhesion, and hypoxia inducible factor 1 (HIF-1) pathway to inhibit GBM progression after simultaneous inhibition of oncomiRs 10b and 21. Hence, we established that BNPs loaded with anti-seed sgPNAstargeting multiple oncomiRs is a promising approach to improve the treatment of GBM, with a potential to personalize treatment based on tumor specific oncomiRs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217366 | GEO | 2023/02/15

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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Anti-seed PNAs targeting multiple oncomiRs for brain tumor therapy

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