With the new treatments that have emerged in the last 5 years for patients with multiple myeloma (MM) there has been substantial progress in terms of patient outcomes. Despite this, researchers continue to seek optimal therapeutic strategies for the disease, and one such approach in the early stages of clinical development is oncolytic virotherapy, an approach that uses viruses to eliminate cancer cells directly or indirectly.1
Oncolytic viruses can infect both normal cells and cancer cells, but they demonstrate a preference for cancer cells due to aberrant cell processes and a cancer-induced downregulation of the host antiviral response.
Signaling pathways that are commonly dysregulated in cancer promote viral infection and/or replication. Activating mutations in the RAS pathway, for example, facilitates infection by double-stranded RNA (dsRNA) viruses. Viruses can activate the PI3K/Akt/mTOR pathway when binding to the cell surface, which promotes viral internalization and replication.
Interferons are important to limiting viral infection during initial stages, yet some tumor cells no longer produce IFN, thus promoting viral infection.
This enhanced infection and replication behavior in cancer cells is exploited by virotherapy, but improved with genetic engineering to increase tumor selectivity and oncolytic activity.
A potential advantage of virotherapy is long-term disease control with a single dose. “Based on our clinical successes and everything else we know about oncolytic viruses and their ability to spread selectively at sites of cancer growth, we think virotherapy can be a single shot treatment in order to bring about long-term disease control,” Stephen J. Russell, MD, PhD, of the Mayo Clinic College of Medicine in Rochester, Minnesota, told Cancer Therapy Advisor.
Several different viruses are being exploited for virotherapy of MM, but most remain in preclinical development including adenovirus, vaccinia virus, Herpes simplex virus type-1, myxoma virus, and coxsackievirus A21.
Several viruses have reached clinical investigation for the treatment of MM, including reovirus, measles virus, and vesicular stomatitis virus.
A phase 1 study of reovirus among patients with relapsed MM resulted in stable disease in 42% of patients. The maximum tolerated dose (MTD) was not reached. In an effort to improve the outcomes with reovirus, a phase 1b trial is ongoing in which reovirus is combined with bortezomib and dexamethasone (ClinicalTrials.gov Identifier: NCT02514382).