Two-Stage Phase I Dose-Escalation Study of Intratumoral Reovirus Type 3 Dearing and Palliative Radiotherapy in Patients with Advanced Cancers

Abstract

Purpose To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses. Experimental Design Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 × 108 and 1 × 1010 TCID50. In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 × 1010 TCID50. End points were safety, viral replication, immunogenicity, and antitumoral activity. Results Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease. Conclusions The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent.

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

“…In addition, GL-ONC1 was investigated in combination with concurrent chemoradiotherapy for locally advanced head and neck cancer (i.e., against a highly toxic standard treatment backbone). We found that intravenous administration of GL-ONC1 was well tolerated in single and multiple escalating doses and was feasible in patients receiving standard chemoradiotherapy, which is consistent with the results of other clinical trials investigating oncolytic viruses (8,9,23,24). The results of this trial also suggest that GL-ONC1 may be a feasible treatment option with less toxic standard treatment approaches, such as concurrent radiation alone, or as monotherapy in a neoadjuvant or adjuvant treatment setting.…”

Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1

“…28 Phase I clinical trials have already begun to explore the feasibility of combining oncolytic viruses with radiotherapy. [29][30][31] A clinical trial has also been undertaken to demonstrate the safety and feasibility of combining IR (single 5 Gy fraction) and oncolytic HSV-1 (JM Markert, personal communication). The data from the current study in part provided the basis for this trial in which radiotherapy is rationally integrated into the viral replicative cycle.…”

Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling

“…Indeed, herpes simplex virus type 1 (OncoVEX GM-CSF ), reovirus (Reolysin) and vaccinia virus (JX-594) have all reached late-stage, randomised clinical trials either as single agent therapies or in combination with cytotoxic chemotherapy. In addition, recent studies have highlighted the fact that combining oncolytic virotherapy with ionizing radiation may lead to synergistic anti-tumor efficacy and translational phase I/II clinical trials have been completed (1,2). However, the reported complex effects of radiation on viral infectivity, replication, gene expression and cytotoxicity mean that detailed mechanistic preclinical studies are an essential prerequisite to trials of new oncolytic viral agents in combination with radiation.…”