SBIR-STTR Award

Non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) are leading cause of cancer death globally. Immune checkpoint inhibitors (CPIs), which block tumor immune-evasion signals and activate T-cell mediated antitumor immunity, have demonstrated clinical efficacy and are approved for several cancers including NSCLC and HCC. Despite this broad spectrum of activity, less than 50% of patients receive any sustained benefit from these compounds. Moreover the majority of patients who achieve a response will relapse within a year. There is an unmet clinical need for therapeutic approaches that overcome resistance and enhance efficacy of CPI therapies. Pharmacodynamics monitoring has been incorporated into clinical trials to define mechanisms of resistance to CPI therapy, indicating that tumors with low levels of immune infiltration, or `cold' tumors, tend to respond poorly to checkpoint inhibition. Oncolytic virotherapy uses engineered viruses to destroy tumor cells and promote antitumor immunity. Several oncolytic virotherapies have been evaluated clinically with the recent approval of an oncolytic Herpesvirus (T-VEC) to treat advanced melanoma. Vyriad is developing Vesicular stomatitis virus (VSV), a potent oncolytic virotherapy platform, as an intravenous therapy for advanced cancer. VSV-IFN?-NIS, an engineered recombinant VSV, has demonstrated potent preclinical efficacy and is currently being tested in a clinical trial for intravenous therapy of patients with advanced cancer. Preclinical studies demonstrate that VSV selectively amplifies in and kills tumor cells resulting in rapid and durable tumor remission following single-shot intravenous therapy in murine tumor models. Intravenous VSV therapy also elicits intratumoral CD8+ T-cell infiltration. The addition of PD-1/PD-L1 blockade extends duration of T-cell infiltration to significantly enhance tumor remission in a murine colorectal tumor model. These data indicate that oncolytic tumor destruction promotes influx of T-cells, while local immunosuppressive signals can be blocked by checkpoint inhibitors to promote activation and amplification of antitumor T-cell responses. These synergistic interactions have the potential to overcome both primary and acquired resistance to single- agent checkpoint inhibitor therapy. Our goal is to clinically advance the combination oncolytic viro- immunotherapy approach to treat patients with CPI refractory NSCLC and HCC. This goal is addressed in this SBIR Fast-track proposal by combining Vyriad's expertise in oncolytic virotherapy development with the world-class expertise of the Mayo Clinic Early Cancer Therapeutics Program. The proposed clinical study will provide critical feasibility and efficacy signals and indicate mode of action to support rapid advancement of this combination oncolytic viro-immunotherapy approach to treat CPI refractory cancer.

Public Health Relevance Statement:
PROJECT NARRATIVE . Non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) are leading causes of cancer death globally and for patients with advanced disease, there are no effective treatment options following failure of first-line therapy. Checkpoint inhibitor immunotherapy has shown promising responses, but most patients remain unresponsive or relapse within a year. Intravenous therapy with an engineered oncolytic vesicular stomatitis virus (VSV) has been shown to synergize with checkpoint blockade to increase durable therapeutic response and our goal is to advance this potent combination therapy approach to improve treatment and quality of life for patients with advanced NSCLC and HCC.

Project Terms:
Address; advanced disease; Advanced Malignant Neoplasm; Biological; Biological Markers; Cancer Etiology; CD8-Positive T-Lymphocytes; Cessation of life; checkpoint inhibition; Checkpoint therapy; Clinic; Clinical; clinical efficacy; Clinical Research; Clinical Trials; Colorectal Neoplasms; Combined Modality Therapy; Correlative Study; Data; Development; Disease Progression; Disease remission; Dose; Drug Kinetics; effective therapy; Engineering; Failure; Goals; Herpesviridae; Immune; Immune checkpoint blockade; Immune checkpoint inhibitor; Immune response; Immunosuppressive Agents; immunotherapeutic virotherapy; Immunotherapy; improved; Infiltration; Intravenous; Malignant Neoplasms; Measurable; Measures; Mediating; melanoma; Modeling; Monitor; Mus; neoplastic cell; Non-Small-Cell Lung Carcinoma; Oncolytic; oncolytic Vesicular Stomatitis Virus; oncolytic virotherapy; Outcome; Patients; PDCD1LG1 gene; Pharmacodynamics; Phase; phase 2 study; preclinical efficacy; preclinical study; Primary carcinoma of the liver cells; programs; Quality of life; Radiology Specialty; Recombinants; Refractory; Relapse; research clinical testing; Resistance; resistance mechanism; response; Running; Safety; safety and feasibility; Signal Transduction; SLEB2 gene; Small Business Innovation Research Grant; Solid Neoplasm; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; therapy outcome; treatment response; tumor; Tumor Burden; Tumor Escape; Tumor Immunity; Vesicular stomatitis Indiana virus; Viremia; Virus; Virus Inhibitors

Non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) are leading cause of cancer death globally. Immune checkpoint inhibitors (CPIs), which block tumor immune-evasion signals and activate T-cell mediated antitumor immunity, have demonstrated clinical efficacy and are approved for several cancers including NSCLC and HCC. Despite this broad spectrum of activity, less than 50% of patients receive any sustained benefit from these compounds. Moreover the majority of patients who achieve a response will relapse within a year. There is an unmet clinical need for therapeutic approaches that overcome resistance and enhance efficacy of CPI therapies. Pharmacodynamics monitoring has been incorporated into clinical trials to define mechanisms of resistance to CPI therapy, indicating that tumors with low levels of immune infiltration, or `cold' tumors, tend to respond poorly to checkpoint inhibition. Oncolytic virotherapy uses engineered viruses to destroy tumor cells and promote antitumor immunity. Several oncolytic virotherapies have been evaluated clinically with the recent approval of an oncolytic Herpesvirus (T-VEC) to treat advanced melanoma. Vyriad is developing Vesicular stomatitis virus (VSV), a potent oncolytic virotherapy platform, as an intravenous therapy for advanced cancer. VSV-IFN?-NIS, an engineered recombinant VSV, has demonstrated potent preclinical efficacy and is currently being tested in a clinical trial for intravenous therapy of patients with advanced cancer. Preclinical studies demonstrate that VSV selectively amplifies in and kills tumor cells resulting in rapid and durable tumor remission following single-shot intravenous therapy in murine tumor models. Intravenous VSV therapy also elicits intratumoral CD8+ T-cell infiltration. The addition of PD-1/PD-L1 blockade extends duration of T-cell infiltration to significantly enhance tumor remission in a murine colorectal tumor model. These data indicate that oncolytic tumor destruction promotes influx of T-cells, while local immunosuppressive signals can be blocked by checkpoint inhibitors to promote activation and amplification of antitumor T-cell responses. These synergistic interactions have the potential to overcome both primary and acquired resistance to single- agent checkpoint inhibitor therapy. Our goal is to clinically advance the combination oncolytic viro- immunotherapy approach to treat patients with CPI refractory NSCLC and HCC. This goal is addressed in this SBIR Fast-track proposal by combining Vyriad's expertise in oncolytic virotherapy development with the world-class expertise of the Mayo Clinic Early Cancer Therapeutics Program. The proposed clinical study will provide critical feasibility and efficacy signals and indicate mode of action to support rapid advancement of this combination oncolytic viro-immunotherapy approach to treat CPI refractory cancer.

Public Health Relevance Statement:
PROJECT NARRATIVE . Non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) are leading causes of cancer death globally and for patients with advanced disease, there are no effective treatment options following failure of first-line therapy. Checkpoint inhibitor immunotherapy has shown promising responses, but most patients remain unresponsive or relapse within a year. Intravenous therapy with an engineered oncolytic vesicular stomatitis virus (VSV) has been shown to synergize with checkpoint blockade to increase durable therapeutic response and our goal is to advance this potent combination therapy approach to improve treatment and quality of life for patients with advanced NSCLC and HCC.

NIH Spending Category:
Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Digestive Diseases; Gene Therapy; Gene Therapy Clinical Trials; Genetics; Immunization; Immunotherapy; Liver Cancer; Liver Disease; Lung; Lung Cancer; Orphan Drug; Rare Diseases; Vaccine Related

Project Terms:
Address; advanced disease; Advanced Malignant Neoplasm; Biological; Biological Markers; Cancer Etiology; CD8-Positive T-Lymphocytes; Cessation of life; checkpoint inhibition; checkpoint therapy; Clinic; Clinical; clinical efficacy; Clinical Research; Clinical Trials; Colorectal Neoplasms; Combined Modality Therapy; Correlative Study; Data; Development; Disease Progression; Disease remission; Dose; effective therapy; Engineering; Failure; Goals; Herpesviridae; Immune; immune checkpoint blockade; Immune checkpoint inhibitor; Immune response; Immunosuppressive Agents; immunotherapeutic virotherapy; Immunotherapy; improved; Infiltration; Intravenous; Malignant Neoplasms; Measurable; Measures; Mediating; melanoma; Modeling; Monitor; Mus; neoplastic cell; Non-Small-Cell Lung Carcinoma; Oncolytic; oncolytic Vesicular Stomatitis Virus; oncolytic virotherapy; Outcome; Patients; PD-1/PD-L1; Pharmacodynamics; pharmacokinetics and pharmacodynamics; Phase; phase 2 study; preclinical efficacy; preclinical study; Primary carcinoma of the liver cells; programmed cell death protein 1; programs; Quality of life; Radiology Specialty; Recombinants; Refractory; Relapse; research clinical testing; Resistance; resistance mechanism; response; Running; Safety; safety and feasibility; Signal Transduction; Small Business Innovation Research Grant; Solid Neoplasm; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; therapy outcome; treatment response; tumor; Tumor Burden; Tumor Escape; Tumor Immunity; Tumor-infiltrating immune cells; Vesicular stomatitis Indiana virus; Viremia; Virus; Virus Inhibitors