Innate immune memory for glioma immunotherapy

About This Grant

ABSTRACT Glioblastomas (GBMs) lack critical innate immune context for productive T cell immune surveillance. Our team developed a live-attenuated recombinant poliovirus, PVSRIPO, that induces MDA5-mediated, sustained type-I interferon (IFN-I) responses in tumor-infiltrating myeloid cells to elicit productive antitumor T cell immunity. I.t. PVSRIPO infusion yielded long-term survival in a subset of recurrent (r)GBM patients (~20%, vs 4% in criterion- matched controls at 3 years) in two independent clinical trials. Long-term survival after PVSRIPO was associated with higher pre-treatment intratumor myeloid and MHC-class II (MHC-II) signatures, baseline inflammation (IL- 1 , TNF) and MHC-II+ monocytes in blood, and IFN-I induction after PVSRIPO infusion. Similarly, IFN-I responsiveness to PVSRIPO in patient-derived GBM ex vivo cultures associated with myeloid inflammatory signatures at baseline. Thus, the induction of IFN-I responses to virotherapy is linked to baseline myeloid inflammation and may determine virotherapy efficacy in patients with rGBM. Environmentally sculpted bone marrow (BM)-resident hematopoietic stem & progenitor cells (HSPCs) have been shown to predetermine antiviral responsiveness of their progeny myeloid cells. In rGBM, intra-patient myeloid profiles are maintained in tumor and blood across multiple time points, implying such durable mechanisms may control systemic myeloid biology. Serendipitously, we discovered that intramuscular (i.m.) vaccination against antigens not expressed by the tumor alters HSPC phenotype and rescues the antitumor efficacy of i.t. immunotherapy (PVSRIPO and STING agonist) in otherwise resistant models. I.m. vaccination caused vaccine-specific CD4+ T cell accumulation, sustained (>1 month) HSPC proliferation and IFN-I signaling, and dendritic cell (DC) progenitor expansion in the BM. These changes were accompanied by higher MHC-II and IFN-I signaling at baseline and stronger IFN-I responses to PVSRIPO therapy in glioma infiltrating DCs. Antitumor effects of i.t. immunotherapy after i.m. vaccination depended on IFN-I, T cells, and MHC-II epitope, and were not reproduced by -glucan—a canonical inducer of trained immunity. Thus, modulating HSPCs may induce antitumor myeloid functions and improve virotherapy sensitivity in gliomas. We hypothesize that IFN-I induction predicts survival after virotherapy, associates with baseline myeloid and HSPC status, and is improved through peripheral vaccine-mediated HSPC modulation. We will test this hypothesis by defining the relationships between IFN-I induction, baseline innate inflammation, HSPC phenotype, and survival after virotherapy in patients with rGBM; determining how HPSC modulation after i.m. vaccination occurs and defining its role in promoting glioma i.t. immunotherapy; and testing whether i.m. vaccination may serve as a novel route to engage cDC1 functions. These studies will define determinants of effective rGBM virotherapy, elucidate the impact of HSPC imprinting on glioma infiltrating myeloid cells, and will test HSPC modulation as a route to engage antitumor myeloid functions.