ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity

Abstract

ONCR-177 is an engineered recombinant oncolytic herpes simplex virus (HSV) with complementary safety mechanisms, including tissue-specific miRNA attenuation and mutant UL37 to inhibit replication, neuropathic activity, and latency in normal cells. ONCR-177 is armed with five transgenes for IL12, FLT3LG (extracellular domain), CCL4, and antagonists to immune checkpoints PD-1 and CTLA-4. In vitro assays demonstrated that targeted miRNAs could efficiently suppress ONCR-177 replication and transgene expression, as could the HSV-1 standard-of-care therapy acyclovir. Although ONCR-177 was oncolytic across a panel of human cancer cell lines, including in the presence of type I IFN, replication was suppressed in human pluripotent stem cell–derived neurons, cardiomyocytes, and hepatocytes. Dendritic cells activated with ONCR-177 tumor lysates efficiently stimulated tumor antigen–specific CD8+ T-cell responses. In vivo, biodistribution analyses suggested that viral copy number and transgene expression peaked approximately 24 to 72 hours after injection and remained primarily within the injected tumor. Intratumoral administration of ONCR-177 mouse surrogate virus, mONCR-171, was efficacious across a panel of syngeneic bilateral mouse tumor models, resulting in partial or complete tumor regressions that translated into significant survival benefits and to the elicitation of a protective memory response. Antitumor effects correlated with local and distant intratumoral infiltration of several immune effector cell types, consistent with the proposed functions of the transgenes. The addition of systemic anti–PD-1 augmented the efficacy of mONCR-171, particularly for abscopal tumors. Based in part upon these preclinical results, ONCR-177 is being evaluated in patients with metastatic cancer (ONCR-177-101, NCT04348916).

Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer

“…In an immunocompetent host, the infection may likely be limited by immune cells recognizing and eliminating infected cells, which may contribute to the e cacy of Synthetic RNA virus. In a syngeneic tumor model sensitive to SVV, Synthetic-SVV increased the number of CD8 T cells and M1 phagocytic macrophages, as generally observed for OVs 29,39,46 . Upregulation of PD-L1 on tumor and myeloid cells provided the rationale for the combination of Synthetic-SVV with anti-PD-1, which demonstrated an improved therapeutic bene t above the monotherapy.…”

“…ICIs are approved for the treatment of SCLC and NSCLC, but the bene ts are limited to a small percentage of patients. In metastatic melanoma, treatments with ICI and OVs are currently being evaluated in the clinic 39,[46][47][48] .…”

A review on the advances and challenges of immunotherapy for head and neck cancer

“…ONCR-177 is a genetically engineered oncolytic HSV-1 carrying five transgenes: IL-12 for activation of natural killer (NK) and T-cells, CCL4 and the extracellular domain of FLT3LG for expansion and recruitment of DCs, and antagonists of PD-1 and CTLA-4 for overcome T-cell exhaustion. To reduce viral replication in normal cells and neuropathic activity as well as selectively targeting tumor cells, ONCR-177 also carries microRNA for the degradation of viral transcripts and is mutated in UL37 [ 58 ]. The combination of ONCR-177 and Pembrolizumab is under phase I clinical trial for the treatment of HNSCC patients (NCT04348916).…”

Oncolytic Herpes Simplex Virus-Based Therapies for Cancer

“…ONCR-177 is an oHSV variant that contains mutations in the UL37 and ICP47 genes, which prevents replication and neuropathic activity in normal cells [ 96 ]. It is armed with five immune-modulatory agents, FLT3LG, IL-12, CCL4, anti-CLTA-4 and anti-PD-1, to increase T cell and NK activation in addition facilitating CD8 + T and dendritic cell recruitment [ 94 , 96 ]. ONCR-177 is in clinical trials to assess its safety and the preliminary anti-tumor efficacy as a monotherapy or in combination with pembrolizumab (anti-PD-1) for treating metastatic solid tumors (NCT04348916).…”