Zhang-Zhi Hu
$24,208
Duke University
North Carolina
National Cancer Institute (NCI)
A defining property of cancers that lack intrinsic immune surveillance is the absence of costimulatory context in myeloid cells—macrophages and dendritic cells (DC)—preventing tumor antigen cross presentation and CD8+T cell priming. There is overwhelming empirical evidence that tumor antigen-specific antitumor immunity requires endogenous, sustained type-I interferon (IFN) release in myeloid cells. To accomplish this, multiple strategies of activating diverse pattern recognition receptors (PRR) were devised for clinical investigation. Several key deficits of such small molecule PRR agonists have prevented breakthrough clinical progress: they lack target specificity for myeloid cells; they do not produce the multilayered, carefully orchestrated innate signaling cascades elicited by innate sensing of natural pathogen challenge; they often produce toxic inflammatory patterns unsuitable for generating antitumor CD8+T cell immunity, eg. due to release of cytokine release syndrome (CRS) cytokines. We are investigating PVSRIPO, the highly attenuated rhino:poliovirus chimera for cancer immunotherapy. PVSRIPO, like its poliovirus parent, has natural target tropism for macrophages/DCs. Infection of myeloid cells is non-cytopathogenic; rather, it elicits endogenous, sustained type-I IFN release due to activation of the MDA5 PRR. The PVSRIPO innate signature is type-I IFN dominant, due to polar TBK1-IRF3 signaling, lacks notorious CRS cytokines, and was shown to mediate polyfunctional antitumor CD8+T cell responses that were qualitatively superior to those elicited by other PRR agonists. CD8+T cells from PVSRIPO-treated tumor-bearing mice exhibited significantly greater antitumor activity in adoptive T cell assays compared to toll-like receptor (TLR)- agonists. Thus, the macrophage/DC-targeted, multilayered and “PRR-contextualized” type-I IFN dominant pattern of PVSRIPO may be optimal for invigorating tumor antigen cross presentation and CD8+T cell priming. We hypothesize that promising results with PVSRIPO in Ph1 clinical trials in recurrent glioblastoma and -melanoma are due to its peculiar and unique type-I IFN signature in myeloid cells; and that intrinsic factors that repress innate responsiveness in myeloid cells pose obstacles to PVSRIPO clinical effectiveness. MDA5/RIG-I-mediated type-I IFN responses in myeloid cells are highly susceptible to prevailing metabolic conditions, in particular glycolytic metabolism/lactate production. Our premise is that unraveling the nexus linking viral RNA replication and MDA5-TBK1-IRF3 innate signaling to glycolytic metabolism will enable new immunotherapy approaches that enhance innate type-I IFN responses with metabolic modifiers. We propose the following Specific Aims: (1) Determine the landscape of glycolytic metabolism in MDA5-sensed viral infection of myeloid cells; (2) Elucidate the role of glycolytic metabolism in the innate inflammatory response in myeloid cells; (3) Determine if modulating glycolytic pathways can bolster anti-glioma responses to PVSRIPO and enhance antitumor immunity after virotherapy.