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IMMU-26. TLR7 ACTIVATION IS ESSENTIAL FOR NK CELLS TO ELIMINATE GLIOMA TUMORS

ABSTRACT: Abstract Our laboratory focuses on understanding anti-glioma immune responses and uses this information to develop new immunotherapies. Endogenous anti-glioma immune responses fail to control the disease due to the development of immune inhibitory mechanisms by glioma tumors. We developed an immune- and gene therapy for active immunization, based on Thymidine Kinase and Flt3L that stimulates a systemic adaptive immune response. This is now in a Phase I Clinical Trial (# NCT01811992). We have previously demonstrated that NK cells and myeloid cells mediate glioma rejection and identified galectin-1 expression as a mechanism of innate immune inhibition. To determine the underlying signaling pathways, we analyzed growth of intracranial NK-sensitive tumors in transgenic mice and in mice treated with blocking/depleting antibodies. We identified TLR7-MyD88 signaling as a key component for glioma rejection. Since IFN ?/? is a major cytokine produced upon TLR7 activation, we blocked the IFN ?/? receptor, which resulted in increased tumor growth. To determine the signaling pathway leading to TLR7-induced IFN ?/? production, we analyzed tumor growth in mice lacking IFN ?/?-regulating transcription factors IRF5 or IRF7. Our data indicate a major role for IRF5 and a minor role for IRF7. TLR7 expression and IFN ?/? secretion are characteristic for pDCs. Depletion of pDCs suggested only a minor role for pDCs in the innate anti-glioma immune response. We propose a model of an innate anti-glioma immune circuit in which a tumor cell-derived TLR7 ligand activates myeloid cells, including pDCs. TLR7 activation results in IRF5/IRF7-mediated secretion of IFN ?/? which in turn promotes glioma rejection by NK cells. Given the major role of TLR7 signaling in glioma rejection, therapeutic TLR7 stimulation could help eliminate GBM by bypassing the innate immune inhibition of glioma. Further characterization of this innate anti-glioma immune circuit will allow us to identify potential therapeutic targets.

SUBMITTER: Shah D

PROVIDER: S-EPMC5692501 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract Background Since the preponderance of pediatric gliomas are mutationally ‘bland,’ immune checkpoint inhibitors are unlikely to mediate therapeutic benefit. Alternately, immunologic response can be induced de novo against pediatric gliomas with mRNA cancer vaccines. Messenger RNA represents a paradigm shift in vaccinology (i.e. COVID-19) given its flexibility, commercialization, and propensity to confer rapid protection with only a single vaccine. Objective We sought to develop a new mRNA platform with an optimized backbone for insertion of both personalized and/or “off the shelf’ (i.e. H3K27M) transcripts for rapid induction of anti-tumor activity against pediatric gliomas. Approach We synthesized an mRNA backbone with optimized 5’ and 3’ UTRs for delivery of gene transcripts pertinent to pediatric brain tumors using a lipid-nanoparticle (NP) delivery vehicle. This vaccine utilizes a novel engineering design that layers tumor derived mRNA into a lipid-nanoparticle (NP) “onion-like” or multi-lamellar package. Results We demonstrate immunogenicity of RNA-NPs delivering either personalized glioma mRNA or H3K27M mRNA. RNA-NPs localize to myeloid cells in murine KR158b brain tumors and activate dendritic cells that supplant regulatory intratumoral myeloid populations inducing antigen-recall response with long-term survivor benefit. Our optimized mRNA backbone yielded significantly improved anti-tumor efficacy compared with commercial backbones. We have shown this approach can be refined for co-delivery of immunomodulatory RNAs (i.e. GM-CSF) and/or delivery of siRNAs targeting immunoregulatory axes (PD-L1) in murine brain tumors (GL261). We have since established safety of RNA-NPs in acute/chronic murine GLP toxicity studies without cross-reactivity to normal-brain, and launched a large-animal canine brain tumor trial which demonstrated RNA-NPs to be feasible, safe and immunologically active. Conclusion RNA-NPs reprogram the brain tumor microenvironment while inducing a glioma-specific immune response. We have since received FDA-IND approval for first-in-human trials (IND#BB-19304) in pediatric patients with high-grade gliomas (PNOC020 study, NCT04573140).

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IMMU-26. TLR7 ACTIVATION IS ESSENTIAL FOR NK CELLS TO ELIMINATE GLIOMA TUMORS

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