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Oncolytic viruses, which preferentially lyse cancer cells and stimulate an antitumor immune response, represent a promising approach to the treatment of cancer. However, how they evade the antiviral immune response and their selective delivery to, and replication in, tumor over normal tissue has not been investigated in humans. Here, we treated patients with a single cycle of intravenous reovirus before planned surgery to resect colorectal cancer metastases in the liver. Tracking the viral genome in the circulation showed that reovirus could be detected in plasma and blood mononuclear, granulocyte, and platelet cell compartments after infusion. Despite the presence of neutralizing antibodies before viral infusion in all patients, replication-competent reovirus that retained cytotoxicity was recovered from blood cells but not plasma, suggesting that transport by cells could protect virus for potential delivery to tumors. Analysis of surgical specimens demonstrated greater, preferential expression of reovirus protein in malignant cells compared to either tumor stroma or surrounding normal liver tissue. There was evidence of viral factories within tumor, and recovery of replicating virus from tumor (but not normal liver) was achieved in all four patients from whom fresh tissue was available. Hence, reovirus could be protected from neutralizing antibodies after systemic administration by immune cell carriage, which delivered reovirus to tumor. These findings suggest new preclinical and clinical scheduling and treatment combination strategies to enhance in vivo immune evasion and effective intravenous delivery of oncolytic viruses to patients in vivo.

Purpose: This study combined systemic administration of the oncolytic reovirus type 3 Dearing (reovirus) with chemotherapy in human subjects. We aimed to determine the safety and feasibility of combining reovirus administration with gemcitabine and to describe the effects of gemcitabine on the antireoviral immune response. Experimental Design: Patients received reovirus in various doses, initially we dosed for five consecutive days but this was poorly tolerated. We amended the protocol to administer a single dose and administered up to 3 × 1010 TCID50. Toxicity was assessed by monitoring of clinical and laboratory measurements. We assessed antibody response by cytotoxicity neutralization assay. Results: Sixteen patients received 47 cycles of reovirus. The two initial patients and one patient in the final cohort experienced dose limiting toxicity (DLT). The DLTs consisted of two asymptomatic grade 3 liver enzyme rises and one asymptomatic grade 3 troponin I rise. Common toxicities consisted of known reovirus and gemcitabine associated side effects. Further analysis showed a potential interaction between reovirus and gemcitabine in causing liver enzyme rises. Grade 3 rises in liver enzymes were associated with concomitant aminocetophen use. Importantly, the duration of the liver enzyme rise was short and reversible. Neutralizing antibody responses to reovirus were attenuated both in time-to-occurrence and peak height of the response. Conclusions: Reovirus at the dose of 1 × 1010 TCID50 can be safely combined with full dose gemcitabine. Combination of reovirus with gemcitabine affects the neutralizing antibody response and this could impact both safety and efficacy of this treatment schedule. Clin Cancer Res; 17(3); 581–8. ©2010 AACR.

We have previously demonstrated the antitumour activity of a treatment combining a replication-defective adenovirus encoding the sodium iodide symporter (NIS), external beam radiotherapy (EBRT) and DNA repair inhibitors. Engineered Measles viruses (MeV) expressing NIS are replication-competent, oncolytic viruses, currently being tested in phase 1 trials. The aim of this study was to evaluate the therapeutic efficacy of a combination of MeV-NIS, EBRT, and a novel checkpoint-1 inhibitor, SAR-020106. This approach was investigated in HN-3, HN-5 and PJ-41 head and neck cancer models. In vitro toxicity was assessed by MTS and clonogenic assays. CD46 (cell receptor for MeV) expression on head and neck cell lines was evaluated by flow cytometry. NIS viral transgene expression was assessed by 125I uptake assays. Apoptosis was evaluated by Caspase Glo® and western blot assays. In vivo therapy experiments were performed in CD1 nude mice with subcutaneous tumour xenografts. In this study, we have demonstrated that EBRT and MeV-NIS had in vitro synergistic antitumour effects in head and neck cancer cell lines. EBRT did increase neither CD46 expression nor viral replication, but significantly increased viral gene expression in infected cells. In vitro, SAR-020106 had synergistic antitumour effect with EBRT. This effect was related to increased apoptosis. In vitro, the combination of MeV-NIS and SAR-020106 was associated with a significantly increased antitumour effect, as compared with control, MeV-NIS alone or SAR-020106 alone (P Disclosure All authors have declared no conflicts of interest.