Kelly, Elizabeth J.

Abstract Background: Oncolytic viruses selectively infect tumors and activate antitumor immune responses via innate and adaptive pathways, which may potentiate the efficacy of immune checkpoint inhibitors. MEDI5395 is a recombinant Newcastle disease virus incorporating a granulocyte macrophage colony-stimulating factor (GM-CSF) transgene that exhibits tumor cell-specific viral replication, stimulates PD-L1 expression, and induces tumor regression in murine and patient-derived xenograft models. Increased T cell recruitment and expression of IFNγ-inducible genes observed in vitro suggest immune activation in the tumor microenvironment (TME). Antitumor activity is enhanced by concurrent PD-L1 blockade. This clinical study is evaluating IV MEDI5395 in combination with the anti-PD-L1 antibody durvalumab in patients with advanced solid tumors. Methods: This is a Phase 1, first-in-human, multicenter, open-label trial (NCT03889275) enrolling patients with breast cancer, colorectal cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, non-small-cell lung cancer or melanoma. Eligibility criteria include relapsed/refractory disease or intolerance to standard therapy after ≥1 prior line of treatment for recurrent/metastatic disease, and ≥1 tumor measurable by RECIST v1.1. Exclusion criteria include rapidly progressing disease precluding a break of ≥8 weeks from systemic therapy, life expectancy ≥12 weeks by GRIm Score, uncontrolled metastatic central nervous system disease, and concomitant immunosuppressive therapy. The initial dose escalation phase will enroll up to 84 patients across all eligible tumor types. Three sequentially ascending dose levels of MEDI5395 will be evaluated. Durvalumab is administered either sequentially or concurrently with MEDI5395, for up to 2 years or until radiologically confirmed disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity. The subsequent dose expansion phase will include 2 cohorts of ~40 patients, each enrolling a single tumor type. The tumor types, MEDI5395 dose level and schedule will be selected based on dose escalation data. On-treatment biopsies of the primary tumor or a metastatic site are required in the dose escalation phase and optional in the dose expansion phase. Primary objectives are evaluating the safety, tolerability and incidence of dose-limiting toxicities of MEDI5395, and identifying the optimal dose/schedule in combination with durvalumab. Secondary objectives include assessing MEDI5395 pharmacokinetics (viremia and GM-CSF transgene expression), pharmacodynamics in the TME, immunogenicity, and initial efficacy in combination with durvalumab. The trial is actively accruing. Citation Format: Grace K. Dy, Diwakar Davar, Evanthia Galanis, Danielle Townsley, Djuro Karanovic, Maria Schwaederle, Beth Kelly, Dmitriy Zamarin, Mitesh Borad, Kevin Harrington. A phase 1 study of IV MEDI5395, an oncolytic virus, in combination with durvalumab in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT244.

ABSTRACT Vesicular stomatitis virus (VSV) has long been regarded as a promising recombinant vaccine platform and oncolytic agent but has not yet been tested in humans because it causes encephalomyelitis in rodents and primates. Recent studies have shown that specific tropisms of several viruses could be eliminated by engineering microRNA target sequences into their genomes, thereby inhibiting spread in tissues expressing cognate microRNAs. We therefore sought to determine whether microRNA targets could be engineered into VSV to ameliorate its neuropathogenicity. Using a panel of recombinant VSVs incorporating microRNA target sequences corresponding to neuron-specific or control microRNAs (in forward and reverse orientations), we tested viral replication kinetics in cell lines treated with microRNA mimics, neurotoxicity after direct intracerebral inoculation in mice, and antitumor efficacy. Compared to picornaviruses and adenoviruses, the engineered VSVs were relatively resistant to microRNA-mediated inhibition, but neurotoxicity could nevertheless be ameliorated significantly using this approach, without compromise to antitumor efficacy. Neurotoxicity was most profoundly reduced in a virus carrying four tandem copies of a neuronal mir125 target sequence inserted in the 3′-untranslated region of the viral polymerase (L) gene.