Oncolytic Maraba Virus MG1 as a Treatment for Sarcoma

Abstract

The poor prognosis of patients with advanced bone and soft-tissue sarcoma has not changed in the past several decades, highlighting the necessity for new therapeutic approaches. Immunotherapies, including oncolytic viral (OV) therapy, have shown great promise in a number of clinical trials for a variety of tumor types. However, the effective application of OV in treating sarcoma still remains to be demonstrated. Although few pre-clinical studies using distinct OVs have been performed and demonstrated therapeutic benefit in sarcoma models, a side-by-side comparison of clinically relevant OV platforms has not been performed. Four clinically relevant OV platforms (Reovirus, Vaccinia virus, Herpes-simplex virus and Rhabdovirus) were screened for their ability to infect and kill human and canine sarcoma cell lines in vitro, and human sarcoma specimens ex vivo. In vivo treatment efficacy was tested in a murine model. The rhabdovirus MG1 demonstrated the highest potency in vitro. Ex vivo, MG1 productively infected more than 80% of human sarcoma tissues tested, and treatment in vivo led to a significant increase in long-lasting cures in sarcoma-bearing mice. Importantly, MG1 treatment induced the generation of memory immune response that provided protection against a subsequent tumor challenge. This study opens the door for the use of MG1-based oncolytic immunotherapy strategies as treatment for sarcoma or as a component of a combined therapy. Sarcomas are a rare and heterogeneous group of aggressive malignant solid tumors that, unlike carcinomas originating from epithelium, arise from a variety of mesenchymal tissues, such as muscle, connective tissue and bone. Sarcomas require a multimodal therapeutic approach that consists of multiagent chemotherapy, surgical resection and radiation. According to the National Cancer Institute, the overall 5-year survival rate for sarcoma patients is 50%, which drops to <20% for cases involving distant metastatic spread. As such, new treatment options for recurrent/metastatic sarcoma are direly needed.Immunotherapy could provide an alternative to chemotherapy yet there has been little focus on sarcoma in this field. This is likely due to sarcoma's heterogeneous nature and the relatively smaller number of patients it affects compared to carcinomas. However, immune checkpoint inhibitors, which have revolutionized the immunotherapy field and that have been very successful to date in melanoma (e.g., anti-CTLA4, anti-PD-1), have so far failed as monotherapies for sarcoma. 1Oncolytic viruses (OVs) constitute another form of an immunotherapy platform that has showed promising results in a broad range of cancers. OVs are engineered to take advantage of several hallmarks of cancer in order to preferentially replicate in tumor cells. Cancer-selective infection by OVs leads to cancer cell lysis and the parallel production of inflammatory cytokines, leading to innate and adaptive immune responses against both virus and tumor.2 OV treatment can lead to profound anti-tumor immune responses and cure...

Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials

“…So, the impact of functional oncolysis on the safety and immunogenicity has not been extended beyond previously published murine data. 14,20,23–25 Toxicity has been associated with acute, massive cytokine release in some immunotherapeutics, such as CAR T-cells. 49 Cytokines were not monitored in this study as their importance in a tumor-free animal is questionable.…”

“…MG1-MAGEA3 is a replication-competent oncolytic rhabdovirus. 14,20,23–27 It was generated by inserting the hMAGE-A3 transgene between the G and L genes of the attenuated MG1 strain of Maraba. Macaques received two doses of 1 × 10 10 or 1 × 10 11 PFU MG1-MAGEA3, delivered intravenously three days apart (Figure 1A).…”

“…The therapeutic activity of oncolytic Maraba MG1 results from multimodal mechanisms: i) systemic administration delivers MG1 to the tumor bed resulting in selective direct oncolysis; 14,20,23–27 ii) infection of tumors by MG1 reprograms the tumor microenvironment (TME) rendering it susceptible to the recruitment and activation of innate and adaptive mediators of antitumor immunity 14,28–30 and iii) circulating MG1 accesses secondary lymphoid organs and rapidly engages the central memory compartment thereby boosting Ad-primed adaptive antitumor immunity. 31 Maraba MG1 has a well-established safety profile within rodents and demonstrates broad oncolytic activity against multiple human and murine cancer cell lines, 14,20,23–25,32,33 primary tumor biopsies, 14,23,28 as well as xenograft and syngeneic tumor models in mice. 23–25,28,29 When administered as an oncolytic vaccine, MG1 exerts remarkable efficacy with complete regressions achieved in aggressive immunocompetent models of melanoma and HPV-positive cancer.…”

“…31 Maraba MG1 has a well-established safety profile within rodents and demonstrates broad oncolytic activity against multiple human and murine cancer cell lines, 14,20,23–25,32,33 primary tumor biopsies, 14,23,28 as well as xenograft and syngeneic tumor models in mice. 23–25,28,29 When administered as an oncolytic vaccine, MG1 exerts remarkable efficacy with complete regressions achieved in aggressive immunocompetent models of melanoma and HPV-positive cancer. 14,20 The present work enabled appraisal of the safety and immunogenicity of oncolytic vaccination in an outbred population of cynomolgus macaques ( Macaca fascicularis ), with increased biologic relevance to humans, enabling the translation of this treatment into a first-in-man clinical trial.…”

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…MG1 showed very good efficacy in various in vitro and in vivo cancer models, including colon, ovarian and sarcoma tumour models [127,129,130]. As with VSV, certain approaches have been developed to improve Maraba virus therapy.…”