Oncolytic immunotherapy and bortezomib synergy improves survival of refractory multiple myeloma in a preclinical model.

The oncolytic reovirus (RV) has demonstrated clinical efficacy and minimal toxicity in a variety of cancers, including multiple myeloma (MM). MM is a malignancy of plasma cells that is considered treatable but incurable because of the 90% relapse rate that is primarily from drug resistance. The systemic nature of MM and the antitumor immunosuppression by its tumor microenvironment presents an ongoing therapeutic challenge. In the present study, we demonstrate that RV synergizes with the standard-of-care MM drug bortezomib (BTZ) and, importantly, enhances its therapeutic potential in therapy-resistant human MM cell lines in vitro. Using the syngeneic Vk*MYC BTZ-resistant immunocompetent transplantable MM murine model, we also demonstrate that mice harboring BTZ-insensitive MM tumors respond to the RV/BTZ combination treatment in terms of decreased tumor burden and improved overall survival (P < .00001). We demonstrate that BTZ augments RV replication in tumor-associated endothelial cells and myeloma cells, leading to enhanced viral delivery and thereby stimulating cytokine release, immune activity, apoptosis, and reduction of the MM-associated immune suppression. We conclude that combined RV/BTZ is an attractive therapeutic strategy with no safety signals for the treatment of MM.

REO-001: A phase I trial of percutaneous intralesional administration of reovirus type 3 dearing (Reolysin®) in patients with advanced solid tumors.

PURPOSE: This open-labeled, phase I clinical trial was designed to determine the safety and tolerability of percutaneous intralesional administration of wild-type oncolytic revovirus type 3 Dearing (Reolysin®) in cancer patients with accessible and evaluable disease, who had otherwise failed to improve on standard cancer interventions. EXPERIMENTAL DESIGN: An escalating dose of Reolysin® starting from up to 10(10) plague forming units (PFU) was administered to each cohort of three patients per dose level. Viral shedding, reovirus neutralizing antibody response, toxicity and clinical response were assessed. RESULTS: Nineteen patients with various advanced solid tumors were treated. The most common toxicities related to treatment were grade 2 (or less) local erythema and transient flu like symptoms. Viral shedding was not seen in cerebral spinal fluid (CSF), urine and stool samples in all patients. Rising viral antibody titres were seen in all patients. In addition, we observed some evidence of local target tumor response activity in 7/19 patients (37 %) at the end of six or more weeks follow-up, with one patient exhibiting a complete response (CR), two a partial response (PR), and four stable disease (SD) to the local injected lesion. CONCLUSIONS: Reolysin® is well tolerated given intralesionaly, with DLT/MTD not reached at a dose of 10(10) PFU. The favorable toxicity profile, lack of viral shedding and possible therapeutic activity has made this unattenuated oncolytic reovirus an attractive cancer therapeutic agent for ongoing clinical studies, including in the setting of locally advanced accessible disease for palliation of symptoms.

REO-10: a phase I study of intravenous reovirus and docetaxel in patients with advanced cancer.

PURPOSE: REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer. EXPERIMENTAL DESIGN: Patients received 75 mg/m(2) docetaxel (day 1) and escalating doses of reovirus up to 3 × 10(10) TCID(50) (days 1-5) every 3 weeks. RESULTS: Twenty-five patients were enrolled, and 24 patients were exposed to treatment, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropenia was seen in one patient, but the maximum tolerated dose was not reached. Antitumor activity was seen with one complete response and three partial responses. A disease control rate (combined complete response, partial response, and stable disease) of 88% was observed. Immunohistochemical analysis of reovirus protein expression was observed in posttreatment tumor biopsies from three patients. CONCLUSION: The combination of reovirus and docetaxel is safe, with evidence of objective disease response, and warrants further evaluation in a phase II study at a recommended schedule of docetaxel (75 mg/m(2), three times weekly) and reovirus (3 × 10(10) TCID(50), days 1-5, every 3 weeks).

The use of immunohistochemistry to determine oncolytic reovirus distribution and replication in-human tumors.

An oncolytic virus is considered a targeted cancer therapy due to its ability to specifically target, replicate in and lyse cancer cells while leaving normal cells unharmed. Over the last few years several tumor selective oncolytic viruses have been developed. These include certain DNA viruses such as adenovirus that have been genetically manipulated to target specific cancer cells by exerting restrictions on the virus at the level of cell entry, viral gene transcription and viral protein translation. There are a variety of RNA viruses being studied as possible cancer therapies including reovirus. Reovirus is intrinsically oncolytic without the need for any genetic manipulation. The inherent oncolytic properties of this virus are derived from the fact that it specifically targets cells with an activated Ras pathway found in many cancer cells. REOLYSIN® is a proprietary formulation of human reovirus type 3 Dearing developed by Oncolytics Biotech Inc. and is the only therapeutic reovirus in clinical development. This review provides an overview of the development of REOLYSIN as a potential cancer therapeutic and the growing role of in situ based molecular pathology methods in providing clinical proof of concept and in guiding clinical development.