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BackgroundONCR-177 is a recombinant oncolytic herpes simplex virus (oHSV) that retains γ34.5 and is engineered to express five immunomodulatory transgenes (IL-12, FLT3LG ECD, CCL4 and anti-PD-1 and anti-CTLA-4 antibodies) for the intratumoral treatment of solid tumors. Attenuation by miRNA leads to selective replication in tumor cells, and mutations in UL37 act as an orthogonal safety strategy. Transgenes elicit potent systemic stimulation of anti-tumor immunity.1 ONCR-177 is being tested in an open-label, multicenter, phase 1 study alone and in combination with pembrolizumab (NCT04348916), for surface lesion injection and intrahepatic injection. Here we present the surface lesion escalation data.MethodsThe objectives were determination of safety and recommended phase 2 dose (RP2D) of ONCR-177 monotherapy in subjects with advanced and/or refractory injectable surface lesions using a modified toxicity probability interval-2 (mTPI-2) escalation design at four dose levels: (Cohort 1: 1×106 PFU in 1 mL, Cohort 2: 1×107 PFU in 1 mL, Cohort 3: 1×108 PFU in 1 mL and Cohort 4: 4×108 PFU in 4 mL). Subjects received ONCR-177 by intratumoral injection once every 2 weeks (up to 10 times) until disease progression or unacceptable toxicity. There was no intrapatient dose escalation.ResultsAs of June 28, 2021, 14 subjects with injectable tumors were enrolled in the dose escalation phase (3 in cohort 1, 4 in cohort 2, 3 in cohort 3 and 4 in cohort 4). Enrolled tumor types included: melanoma (3), breast (3), anal squamous cell (1), lung (1), duodenal (1), basal cell (1), chondrosarcoma (1), thyroid (1), oropharyngeal (1) and papillary renal cell (1). Subject median age was 67 years. Median number of prior lines of therapy was 4 (range 2–11), including 11 of 14 subjects with prior immunotherapy. Nine subjects were HSV-1 seropositive at baseline, 4 were negative, one was unknown. Treatment-related Adverse Events were all Grade 1–2. Most commonly reported were: cytokine release syndrome (2 occurrences in Cohort 4), fatigue, nausea, chills, headache, decreased appetite, hypotension, and injection site pain. There were no dose-limiting toxicities. The RP2D was selected as 4×108 PFU in 4 mL every 2 weeks up to 10 doses. Clinical data, including safety, viral shedding and exploratory biomarker data including peripheral payloads, peripheral cytokines and immune infiltration and PD-L1 expression in the tumor microenvironment will be presented.ConclusionsONCR-177 monotherapy in heavily pretreated subjects with advanced, injectable, solid tumors at the RP2D was safe and tolerable. Enrollment at the RP2D is underway in monotherapy expansion.Trial RegistrationNCT04348916ReferencesHaines BB, Denslow A, Grzesik P, Lee JS, Farkaly T, Hewett J, Wambua D, Kong L, Behera P, Jacques J, et al. ONCR-177, an Oncolytic HSV-1 Designed to Potently Activate Systemic Antitumor Immunity. Cancer Immunol Res 2021;9: 291–308Ethics ApprovalThis study was approved by the following institutional Ethics Boards:-University Health Network Research Ethics Board (ID Number: 20-5069)-Integreview IRB (ID Number RM 694) -WCG IRB (ID Number: 20200150)-Advarra (ID Number: 00000971)-Roswell Park IRB (ID Number: STUDY00001189/P-553719)-The Ohio State University Cancer IRB (ID Number: 2020C0139) -Dana Farber Cancer Institute IRB (ID Number 354020)All participants gave informed consent before taking part in this clinical trial.

Oncolytic viruses (OV) have shown great potential to improve clinical outcomes when dosed intratumorally, however, their therapeutic efficacy when intravenously administered is likely limited by the rapid emergence of neutralizing antibodies. To overcome this limitation, we developed Synthetic RNA viruses consisting of a replication competent viral genomic RNA (vRNA) encapsulated within a lipid nanoparticle (LNP) for IV administration. Upon dosing and delivery of this infectious RNA payload, the vRNA initiates viral replication and virus production in neoplastic cells leading to oncolysis and tumor destruction. This formulation enables repeat intravenous dosing of a replication competent oncolytic virotherapy even in presence of circulating neutralizing antibody to the virus. Here we present ONCR-021, an LNP formulation of Coxsackievirus A21 (CVA21) vRNA. ONCR-021 vRNA encodes a novel ICAM1-dependent strain of CVA21 that results in greater in vitro and in vivo oncolysis compared to the previously described CVA21 Kuykendall strain. ONCR-021 is broadly oncolytic in cancer cell lines in vitro and is intended for clinical development in NSCLC, RCC, and HCC based upon the viral tropism. IV-administration of ONCR-021 vRNA results in rapid initiation of viral replication, oncolysis, and potent anti-tumor efficacy, even in the presence of circulating CVA21 neutralizing antibodies. This efficacy is principally driven by CVA21 amplification in situ after delivery to tumor cells and we demonstrate viral replication, virion production and spread within the tumor after dosing. We also observe only modest and transient production of CVA21 in healthy tissues of transgenic mice expressing the CVA21 entry receptor human ICAM1. Consistent with these findings, high doses levels of ONCR-021 were well-tolerated in this model. Altogether, these preclinical data support the development of ONCR-021, a novel synthetic oncolytic virus designed to overcome the challenges of repeat intravenous administration of viral immunotherapy for the treatment of disseminated cancers. Citation Format: Jeffrey Bryant, Agnieszka Denslow, Jacqueline Hewett, Lingxin Cong, Ana De Almeida, Jennifer Lee, Judy Jacques, Sonia Feau, Daniel. Wambua, Adrienne Yanez, Pam Shou-Ping Wang, Jessica Deterling, Matthew Scott, Jason Auer, Brian B. Haines, Christophe Quéva, Lorena Lerner, Edward M. Kennedy. ONCR-021 as a systemic intravenous synthetic RNA virus immunotherapy for the repeat treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 383.