Document text
Principal Investigator: Christophe Queva
Organization: ONCORUS, INC.
Fiscal Year: 2019
Award: $299,976
Funding agency: National Cancer Institute
The most aggressive form of brain malignancies, glioblastoma multiforme (GBM) represents a particularly acute
unmet medical need. GBM are highly invasive and do not respond to immune checkpoint inhibition due to their
suppressive microenvironment. Oncolytic viruses engineered to selectively replicate and kill malignant GBM
cells and to express transgenes that stimulate antitumor immunity are attractive approaches to improve patient
outcomes as monotherapy and in combination with anti-PD-1 therapeutics. Preliminary data achieved with a
prototypical oncolytic herpes simplex virus (oHSV) armed with ULBP3, a ligand for KLRK1 a stimulatory receptor
expressed in CD8 and NK cells and featuring the improvements in oncolytic potency, micro-RNA attenuation
and payload capacity designed by Oncorus demonstrated a significant survival benefit after a single intratumoral
injection in a genetically inducible model of GBM designed to recapitulate the major genetic alterations and
pathobiology of GBM. Moreover, injection of oHSV expressing ULBP3 in one tumor mass resulted in an abscopal
anti-tumor response in the uninjected tumor mass. This result was surprising since the human-specific ULBP3
gene product does not recognize the mouse KLRK1 receptor and primarily acts through the recruitment of
macrophages and microglia, suggesting a novel receptor for ULBP3 on these cells both in mouse and human.
Preliminary studies identified tissue factor, a transmembrane receptor with a role in coagulation and signaling in
GBM as this new receptor. We aim to investigate the mode of action of ULBP3 in GBM models and confirm this
novel interaction. We propose to further exploit these initial findings for the design of an optimized armed oHSV
for the treatment of GBM. As a first step, we will tailor the unique safety features of Oncorus oHSV, the selection
of micro-RNA highly expressed in healthy brain tissues and lost in GBM to insert complementary micro-RNA
target sequences in multiple genes essential to HSV replication, thus restraining viral replication to malignant
cells. MicroRNA 124, 128 and 137 that showed strong differential expression are likely candidates. Additionally,
payloads, including IL-12, and PD-1 and CD47 antagonists, that have been validated in GBM preclinical models,
and that may complement the activity of ULBP3 will be tested stepwise in GBM cell lines and tumor cells for
oncolytic activity, expression and in vivo efficacy in syngeneic GBM models and in state-of-the-art inducible
genetic models. From these data the optimized combination of payloads will be introduced into our oHSV in
order to create the most potent vector and clinical candidate for future human trials.
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Terms: <ACT2><AT744.1><Act-2><Acute><Antibodies><Antigen-Presenting Cells><Antineoplastic Vaccine><Antitumor Response><Attenuated><Autologous><Blood Coagulation Factor III><Body Tissues><Brain><Brain Nervous System><CCL4><CCL4 gene><CD142 Antigens><CD152><CD152 Antigen><CD152 Antigen Gene><CD152 Gene><CD47><CD47 Antigen><CD47 Glycoprotein><CD47 gene><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CTLA 4><CTLA-4 Gene><CTLA-4 antigen><CTLA4><CTLA4 Protein><CTLA4 gene><CTLA4-TM><Cancer Vaccines><Cancers><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Line><Cell Signaling><CellLine><Cells><Chemokine (C-C Motif) Ligand 4><Chemokine, CC Motif, Ligand 4><Clinic><Clinical><Clinical Trials><Clotting><Coagulation><Coagulation Factor III><Coagulation Process><Coagulin><Complement><Complement Proteins><Complex><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte Protein 4 Gene><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Antigen 4 Gene><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4 Gene><Cytotoxic cell><Data><Dendritic Cells><Development><Disease><Disorder><Edodekin Alfa><Encephalon><Engineering><Essential Genes><FLT 3 Ligand><FLT3 ligand><FLT3L><FLT3LG><FLT3LG gene><FMS-Related Tyrosine Kinase 3 Ligand Gene><FMS-Related Tyrosine Kinase-3 Ligand><Factor III><Fatal Outcome><Functional RNA><Future><General Viruses><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic Models><Genetic defect><Glioblastoma><Glomerular Procoagulant Activity><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><HNSCC><HSV><HSV-1><HSV1><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><Herpes Simplex Virus><Herpes Simplex Virus 1><Herpes Simplex Virus Type 1><Herpes labialis Virus><Herpesvirus 1><Hortega cell><Human><IL-12><IL12><Immune><Immune Activation 2><Immune response><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunotherapy><Induction Therapy><Injections><Integrin-Associated Protein><Interleukin-12><Intracellular Communication and Signaling><K lymphocyte><Lead><Ligands><MER6><MHC Receptor><MIP1B><MIP1B1><Macrophage Inflammatory Protein 1-Beta><Major Histocompatibility Complex Receptor><Malignant><Malignant - descriptor><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Medical><Messenger RNA><Mice><Mice Mammals><Micro RNA><MicroRNAs><Microglia><Modeling><Modern Man><Murine><Mus><Mutation><Myeloid-derived suppressor cells><NEOADJ><NK Cells><NKSF><Natural Killer Cell Stimulatory Factor><Natural Killer Cells><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplasm Vaccines><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Oncogenic Viruses><Oncolytic><Oncolytic viruses><PD 1><PD-1><PD1><PD1 gene><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pattern><Pb element><Pre-Clinical Model><Preclinical Models><Prothrombinase><Receptor Protein><Receptors, Antigen, T-Cell><Recombinant DNA Technology><Research><Role><SCCHN><SCYA4><SLEB2 gene><STK1-ligand><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Simplexvirus><Small Inducible Cytokine A4><Solid><Strains Cell Lines><Surface Antigen Identified by Monoclonal Antibody 1D8><T-Cell Activation><T-Cell Receptor><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Thromboplastin><Tissue Factor><Tissue Factor Procoagulant><Tissue Thromboplastin><Tissues><Transgenes><Tumor Antigens><Tumor Cell><Tumor Immunity><Tumor Vaccines><Tumor Viruses><Tumor-Associated Antigen><Tumor-associated macrophages><Untranslated RNA><Urothromboplastin><Veiled Cells><Viral Diseases><Virus><Virus Diseases><Virus Replication><accessory cell><allergic/immunologic body system><allergic/immunologic organ system><anti-PD-1><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD1><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-programmed cell death protein 1 antibodies><anti-tumor immune response><anti-tumor immunity><anti-tumor response><antiPD-1><antiPD1><antitumor immune response><antitumor immunity><arm><attenuation><biological signal transduction><brain tissue><cancer antigens><cancer cell><cell killing><check point inhibition><checkpoint inhibition><clinical candidate><clinical development><cultured cell line><customized therapy><customized treatment><cytotoxic T-lymphocyte antigen 4><design><designing><developmental><differential expression><differentially expressed><experiment><experimental research><experimental study><flk2 ligand><flk2-flt3 ligand><flt3 ligand protein><gene product><genetically engineered><genome mutation><gitter cell><glioblastoma multiforme><heavy metal Pb><heavy metal lead><herpes simplex i><host response><human disease><immune activation><immune check point inhibition><immune checkpoint inhibition><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunoresponse><improved><in vivo><individualized medicine><individualized patient treatment><individualized therapy><individualized treatment><inflammatory environment><inflammatory milieu><innovate><innovation><innovative><lead candidate><mRNA><macrophage><malignancy><meetings><mesoglia><miRNA><miRNAs><microglial cell><microgliocyte><mouse model><murine model><neoplasm/cancer><neoplastic cell><neuronal><neuronal transport><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><next generation><noncoding><novel><novel therapeutic approach><novel therapeutic intervention><novel therapy approach><oHSV><oncolytic herpes simplex virus><perivascular glial cell><pre-clinical><preclinical><prevent><preventing><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><promoter><promotor><receptor><recruit><sle2><social role><spongioblastoma multiforme><stem cell tyrosine kinase 1 ligand><systemic lupus erythematosus susceptibility 2><systemic toxicity><tailored medical treatment><tailored therapy><tailored treatment><thymus derived lymphocyte><transcriptional differences><tumor><tumor-specific antigen><unique treatment><vaccine for cancer><vector><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease>