Arming, Pseudotyping, and Enhancing the Efficacy of Oncolytic Measles Virus for a Better Cancer Therapeutic

Abstract

Everyone knows someone affected by cancer. It is a heterogeneous malignancy requiring different approaches depending on the source, aggressiveness, and stage of the disease. To this end, innovative cancer therapies are required to conquer the unique obstacles posed by each type of cancer. One emerging therapeutic avenue employs the use of oncolytic viruses. Oncolytic viruses are predominantly attenuated viruses that specifically replicate in cancerous cells, which often have defective anti-viral responses, while leaving normal tissue unaffected. The inability of certain cancers to counter viral infections stems from a defective interferon pathway utilized by the malignant cells for unregulated proliferation. This ingenious exploitation of the cancer’s double-edged attribute led to numerous oncolytic virus clinical trials presently culminating in an approved oncolytic virus therapy, Talimogene laherparepvec, for the treatment of advanced melanoma. Oncolytic measles virus is currently being evaluated in several pre-clinical and clinical cancer trials. This virus offers many advantages as a replicating cancer therapeutic such as an excellent safety profile, oncotropic traits, and permissiveness for enhancement via genetic engineering. Even so, further improvements of oncolytic measles virus may be required to overcome the various complexities that each type of cancer poses. Some concerns are also inherent to the use of measles virus itself, such as pre-existing neutralizing antibodies towards the virus from routine immunization. This thesis outlines three distinct projects which aim to improve oncolytic measles virus as a cancer therapeutic. Firstly, a novel pseudotyping platform for oncolytic measles virus is described as an efficient and robust system for viral envelope exchange for the purpose of evading neutralizing antibodies. Secondly, oncolytic measles virus armed with granzyme B displayed increased oncolytic and proinflammatory activity. Finally, synergizing oncolytic measles virus with viral sensitizers enhanced the replication and cancer cell killing ability of the virus in both human and murine cancer models. Each project uniquely demonstrated advances in improving oncolytic measles virus so it may surmount the current challenges facing it as a cancer therapeutic.