Design of ONCR-177 base vector, a next generation oncolytic herpes simplex virus type-1, optimized for robust oncolysis, transgene expression and tumor-selective replication

ONCR-177 is a novel oncolytic herpes simplex virus type-1 (oHSV-1) developed for the treatment of metastatic cancers. ONCR-177 base vector, ONCR-159, has been optimized to elicit potent oncolysis, even in presence of host cell antiviral response by keeping the neurovirulence gene ICP34.5. ONCR-159 oncolytic activity and replication in human cancer cell lines is less sensitive to IFNα compared to ICP34.5 deleted oHSV. A dual bidirectional promoter enables the expression of 5 transgenes in ONCR-177: the NK and T cell activating cytokine IL-12, the chemokines CCL4 and FLT3LG (extracellular domain) to allow for expansion and recruitment of classical dendritic cells, and antagonists to the clinically validated immune checkpoints PD-1 and CTLA-4 to counter T cell exhaustion. To ensure selective replication in cancer cells, ONCR-177 utilizes a unique conditional-lethal strategy in which tissue specific microRNA (miRNA)-binding cassettes (miR-T) are inserted into early genes essential for viral replication and in ICP34.5. We leveraged our comprehensive normal and malignant tissue expression analysis to identify highly expressed tissue-specific miRNAs and tailored their selection to ONCR-177 clinical indications of interest. In addition, we performed a siRNA screen to identify essential HSV-1 genes for replication in which miR-T cassettes were introduced. This attenuation strategy dramatically reduced transgene expression and viral replication in healthy tissues expressing the selected miRs without compromising oncolytic activity in cancer cells. ONCR-159 and ONCR-177 demonstrate potent tumor cell killing in human cell lines in vitro and in 3 syngeneic tumor models in vivo. Furthermore, mutations that inhibit axonal retrograde transport have been introduced in ONCR-159 and ONCR-177 (Richards et al., 2017) providing an orthogonal protection of the nervous system and preventing virus of latency.In conclusion, ONCR-177 has been optimized to be a safe and efficacious therapy for the treatment of solid tumors, eliciting direct oncolysis and enhancement of antitumor immune response warranting its evaluation in phase 1 clinical trial. Richards et al., 2017. PLoS Pathog 13(12): e1006741. Citation Format: Edward M. Kennedy, Terry Farkaly, Prajna Behera, Allison Colthart, Caitlin Goshert, Judy Jacques, Kyle Grant, Peter Grzesik, Jennifer Lerr, Laura Viggiano Salta, Lorenz Ponce, Caroline Web, Brian Haines, Agnieszka Denslow, Jacqueline Gursha, Mitchell Finer, Christophe Queva, Lorena R. Lerner. Design of ONCR-177 base vector, a next generation oncolytic herpes simplex virus type-1, optimized for robust oncolysis, transgene expression and tumor-selective replication [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1455.