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Principal Investigator: Matthias Gromeier
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $358,773
Funding agency: National Cancer Institute
Priming of antitumor immunity relies on a specialized subset of conventional Dendritic Cells (cDC1s), CD103+
DCs, that have unique capabilities of trafficking tumor antigens to lymph nodes for cross-presentation. The critical
role of cDC1s in cancer immune surveillance make them highly coveted targets for immunotherapy; however,
their scarcity, the difficulty of specifically engaging DCs, and the suppressive tumor microenvironment (TME)
pose severe obstacles. We are investigating immunotherapy with attenuated, recombinant poliovirus (PV),
PVSRIPO, because of the naturally evolved tropism of PV for DCs. In humans or chimpanzees, oral PV infection
leads to remarkably effective targeting of CD11c+DCs in peripheral (gastrointestinal) and lymphoid tissues.
PVSRIPO, engineered with an IRES from human rhinovirus type 2, lacks cytopathogenicity in normal cells, eg.
DCs. Rather, DC infection yields ‘sustained’ type-I interferon (IFN) responses elicited by specific viral dsRNA
patterns that engage the PV pattern recognition receptor (PRR) MDA5. Mechanistic investigations of PVSRIPO
treatment in ex vivo human tumor slices revealed that: (i) the main outcome is sustained type-I IFN release from
myeloid cell subsets in the non-malignant TME; (ii) PVSRIPO’s unique innate imprint provides optimal DC
activation stimuli for CD4+T cell TH1-polarization and CD8+T cell priming; (iii) PVSRIPO’s ‘PRR-contextualized’
IFN response induces polyfunctional GzmB+, IFNg+, T-bet+ antitumor CD8+T cells that control tumor growth after
adoptive transfer. We reported very promising Ph1 clinical trial results with PVSRIPO in challenging
indications: recurrent glioblastoma and recurrent, nonresectable melanoma. Our premise is that PVSRIPO
therapy recruits cDC1s, leads to local infection of these cells, induces migration to lymph nodes/spleen,
and stimulates tumor antigen cross-presentation via the intrinsic innate inflammatory signature it elicits.
We propose mechanistic and translational studies to gain insight into targeting of DCs by PVSRIPO, the way
sublethal infection of distinct myeloid subsets activates tumor antigen cross-presentation, and rational means of
enhancing DC engagement by intranodal virus administration. We propose the following Specific Aims: (1)
Unravel mechanisms of cDC1 recruitment, activation, and lymph node migration upon PVSRIPO infection of the
TME. (2) Determine the mononuclear phagocyte compartment(s) that mediate PVSRIPO antitumor effects; test
the roles of T cell-intrinsic IFN signaling and chemotaxis. (3) Reinforce cDC1 engagement by perinodal delivery
or upon infection of the PVSRIPO-reactive glioma myeloid infiltrate.
Significance: these studies explore a unique opportunity for effectively engaging CD103+DCs in tumor antigen
cross-presentation and CD8+T cell priming, based on the natural tropism for DCs and unique innate inflammatory
imprint of PVSRIPO. The long-term objective of this research is to provide means for re-instating effective cancer
immune surveillance in patients by overcoming tumor-associated deficits in DC function and CD8+T cell priming.
Terms: <ABC17><ABCB2><Adoptive Transfer><Antigen-Presenting Cells><Antigens><Attenuated><Autopsy><Brain><Brain Nervous System><Brunhilde Virus><CD11b><CD11c><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CNS lymphatic system><CR3A><Cancer Patient><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Locomotion><Cell Migration><Cell Movement><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Cervical Lymph Node><Cervical lymph node group><Chemotaxis><Chimp><Chimpanzee><Clinical><Clinical Trials><Cross Presentation><Cytoplasm><Cytotoxic cell><D6S114E><Dendritic Cells><Dendritic cell activation><Disease><Disorder><Double-Stranded RNA><Encephalon><Engineering><Extensive Disease><Focal Infection><Generalized Disease><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Human><Human poliovirus><IFIH1><IFN><IRES><ITGAM><ITGAM gene><ITGAX><ITGAX gene><Immune><Immune Surveillance><Immune mediated therapy><Immunes><Immunity><Immunologic Stimulation><Immunologic Surveillance><Immunologic Surveillances><Immunological Stimulation><Immunological Surveillance><Immunological Surveillances><Immunologically Directed Therapy><Immunology><Immunostimulation><Immunosurveillance><Immunotherapy><In Vitro><Infection><Infiltration><Inflammatory><Injections><Interferon Induced With Helicase C Domain 1><Interferon Type I><Interferons><Internal Ribosome Entry Segment><Internal Ribosome Entry Site><Intracellular Communication and Signaling><Investigation><K lymphocyte><Lymph Node Reticuloendothelial System><Lymph System><Lymph node proper><Lymphatic Network><Lymphatic System><Lymphatic System Reticuloendothelial System><Lymphatic Tissue><Lymphatic nodes><Lymphoid Tissue><MAC1A><MDA 5><MO1A><Macaca><Macaque><Macrophage><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Mediating><Melanoma><Mice><Mice Mammals><Modeling><Modern Man><Mononuclear><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Mφ><NK Cells><Natural Killer Cells><Necrosis><Necrotic><Neuroglial Neoplasm><Neuroglial Tumor><Nodal><Non-Malignant><Normal Cell><Oral><Outcome><PSF1><Pan Genus><Pan Species><Pathogenicity><Patients><Pattern><Pattern recognition receptor><Peripheral><Phagocytes><Phagocytic Cell><Polio Virus><Poliovirus><Poliovirus Type 1><RING4><RNA Viruses><Radiography><Reaction><Receptor Signaling><Recombinants><Recurrence><Recurrent><Reporting><Repression><Research><Resistance><Resolution><Rhinovirus><Ribosome Entry Site><Roentgenography><Role><Schedule><Signal Transduction><Signal Transduction 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system><glioblastoma multiforme><glymphatic clearance pathway><glymphatic pathway><glymphatic system><glymphatic-lymphatic system><glymphatics><immune check point blockade><immune checkpoint blockade><immune microenvironment><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><imprint><in vivo><infection localized><insight><local infection><lymph gland><lymph nodes><lymphnodes><lymphoid structures><malignancy><melanoma differentiation associated gene 5><melanoma differentiation associated protein 5><migration><necropsy><neoplasm/cancer><neuroglia neoplasm><neuroglia tumor><nonmalignant><paravascular system><pathogen><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><poliomyelitis virus><postmortem><radiologic imaging><radiological imaging><recruit><resistant><resolutions><response><safety study><sensor><social role><spatiotemporal><spongioblastoma multiforme><thymus derived lymphocyte><trafficking><translational study><tumor><tumor growth><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions><tumor-specific antigen>