Cell Carriage, Delivery, and Selective Replication of an Oncolytic Virus in Tumor in Patients

Abstract

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.

Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma

“…Innate immunity and complement may impede delivery of oncolytic viruses, especially with the intravenous approach (27). However, transportation by cells may also protect virus during intravenous delivery, despite the presence of neutralizing antibodies prior to infusion (28). The role of adaptive immunity in limiting the benefit of repeated administrations of virus is unknown and requires additional study.…”

Re-engineering Vesicular Stomatitis Virus to Abrogate Neurotoxicity, Circumvent Humoral Immunity, and Enhance Oncolytic Potency

“…Recently, two clinical studies have demonstrated that certain OVs can be delivered to tumor beds despite the presence of some level of circulating antibody (47,48). Nevertheless, it is widely believed that nAbs that arise during therapy will significantly abrogate therapeutic efficacy of repeated systemic OV applications (13,49).…”

Immune Checkpoint Inhibitor Combinations in Solid Tumors: Opportunities and Challenges

“…In both preclinical and clinical studies, it is clear that a robust and specific infection of tumor bed oncolytic viruses is achievable after intravenous infusion or i.t. injection using various platforms [101][102][103]. I.t.…”