We conducted a literature search of OV clinical studies over 20 years and identified 97 trials representing 3,233 patients. We report the most common viruses, transgenes, indications, routes, and correlative biomarker analyses used. Only a limited number of viruses and payloads have entered the clinic. There is an opportunity to optimize clinical OV study designs to improve OV therapy.

Tumor immune heterogeneity represents one of the key impediments to the efficacy of immunotherapies such as immune checkpoint blockade. Using oncolytic Newcastle Disease Virus (NDV) as a model, we demonstrate that intratumoral NDV therapy increases TCR repertoire breadth and clonal overlap across the NDV-treated and distant tumor sites. On a single-cell level, we find that dominant T cell phenotypes expanded in NDV-treated tumors are distinct from the distant tumors and is associated with unique dominant TCRs. Understanding of the interplay between the virus-specific and tumor-specific T cells will be key to development of engineered oncolytic viruses with maximal immunotherapeutic potential.

Mutations in the IFNγ response pathway is one of the best-established mechanisms of immune checkpoint inhibitor (ICI) resistance. Disablement of the anti-viral IFNγ response should render melanomas sensitive to oncolytic viruses (OVs). Our study provides mechanistic evidence supporting OVs as a precision-medicine strategy to treat ICI-resistant and treatment-naïve melanomas with defects in the IFNγ pathway, and also demonstrates the potential clinical utility of JAK inhibitor-OV combination as a melanoma therapy. 

Oncolytic herpes simplex virus (oHSV) is both directly cytotoxic and immunotherapeutic. Combination therapies, including arming oHSV with therapeutic transgenes or systemic administration of pharmacological agents, can enhance efficacy, especially when they alter the tumor microenvironment. We will discuss preclinical combination studies with oHSV expressing IL-12 that impacted immunological outcomes beneficially and adversely.

Intratumoral administration of oncolytic viruses (OV) is preferred in clinical environment, but inadequate intratumoral retainment and shedding of OVs to normal tissues limit the potency and safety of virotherapy. To address this challenge, we have developed several different hydrogel systems to prolong the antitumor activity of OV, as well as inhibiting nonspecific shedding of virions to normal tissues to improve its safety profile.

Candel Therapeutics is a clinical stage biopharmaceutical company developing oncolytic viral immunotherapies. Its engineered adenoviral and herpes simplex virus gene constructs are designed to induce cell death in cancer cells in a pro-inflammatory tumor microenvironment, resulting in a specific immune response against the injected tumor and uninjected metastases. Candel’s clinical pipeline is focused on lung cancer, high-grade glioma, pancreatic cancer, and prostate cancer. The Candel discovery platform is based on HSV.

Replimune is developing a series of multiply armed oncolytic immunotherapies based on a high potency clinical strain of HSV, designed to provide sequentially more potent local tumor destruction and systemic immune activation to provide patient-specific immunization against the patient's particular complement of tumor antigens. Compelling clinical safety and efficacy data has been generated with RP1 (expresses GALV-GP R- and GM-CSF) and RP2 (additionally expresses anti-CTLA-4), including in combination with anti-PD1 therapy, and RP1 is currently being assessed in two registration-directed clinical trials (in CSCC and anti-PD1 failed melanoma). RP3 (additionally expresses CD40L and 4-1BBL, but does not encode GM-CSF) is currently in a Phase 1 clinical trial, for which initial data is anticipated towards the end of 2021.

Clinical development of retroviral replicating vectors (RRV) for prodrug-activator virotherapy of cancer has been pursued for over a decade. Early phase clinical trials in recurrent high-grade glioma patients showed promising evidence of therapeutic efficacy and durable survival. While an international Phase III trial completed in late 2019 did not meet overall endpoints, the median number of prodrug cycles administered was found to be inadequate, and subsequent analysis revealed highly significant survival in pre-specified patient subgroups, as compared to randomized matched controls. Further clinical investigation is on-going, and next-generation vectors with enhanced cytotoxicity and activation of anti-tumor immunity are being developed.

CG0070 is a conditionally replicating oncolytic serotype 5 adenovirus designed to preferentially replicate in and kill cancer cells, and to encode human granulocyte macrophage-colony stimulating factor (GM-CSF). In CG0070, the human E2F1 promoter drives expression of the essential El viral genes and restricts viral replication to retinoblastoma (Rb) gene pathway defective tumor cells, selectively killing these cells with minimal damage to normal tissues.  Rb mutations and/or an over expression of the transcription factor E2F1 have been correlated with relatively poor overall survival in patients with non-muscle invasive bladder cancer (NMIBC). 

Our preclinical data suggest that CG0070 in addition to its direct oncolytic effect after local treatment may also induce a systemic tumor specific immunity such that distant tumor metastases may be affected. 

CG0070 is a cancer selective, GM-CSF expressing adenovirus engineered to selectively replicate in tumor cells with retinoblastoma tumor suppressor gene pathway defects.  Clinical efficacy and safety have been demonstrated across 2 clinical trials targeting non-muscle invasive bladder cancer following BCG failure.  Ongoing studies targeting bladder cancer, including a phase 3 registration study in non-muscle invasive bladder cancer, and other tumor types will be reviewed. 

Oncorus innovative Synthetic RNA virus platform is designed to enable repeat intravenous administration of viral immunotherapy. Synthetic RNA viruses are comprised of viral RNA genomes encapsulated in lipid nanoparticles that by-pass virus neutralizing antibodies. Synthetic RNA viruses selectively replicate and produce infectious virions within tumor cells, promoting immune cell infiltration and response to checkpoint inhibitors. They are well tolerated and demonstrate potent and durable anti-tumor activity.

Extracellular matrix (ECM) constitutes a major non-cellular component in the tumor microenvironment (TME), and promotes malignant phenotypes and progression of cancers. How ECM impacts the activity of virus immunotherapy of cancer, however, remained largely unknown. We show that tumor hyaluronan degradation by hyaluronidase-armed oncolytic adenovirus ICOVIR17 increased immune cell infiltration and PD-L1 levels in murine glioblastoma. Combination therapy of ICOVIR17 and PD-1 blockade induced long-term survivals, revealing hyaluronan in the TME as a previously underappreciated therapeutic target in oncolytic virus immunotherapy.     

This presentation will discuss: Next-generation oncolytic virus therapies will ideally be delivered intravenously; modifications of the viral backbone can increase systemic delivery, even in the face of pre-existing anti-viral immunity; and the addition of therapeutic trans gene and transgender combinations can result in a platform of potent systemic therapies