Oncolytic viruses preferentially target tumor cells — something clinicians first suspected more than a century ago, based on anecdotes about viral infection and spontaneous tumor regression.

“They have a predilection to lyse cancer cells with minimal damage to normal, healthy cells,” said Dmitriy Zamarin, MD, PhD, of the Memorial Sloan Kettering Cancer Center in New York, New York. “They replicate mainly in tumor cells.”

Alone, virotherapy has shown limited success at long-term tumor eradication. Understanding of just how they work has evolved dramatically over recent years, however, suggesting a potential new combinatorial role for these investigational agents alongside immunotherapies.

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It was long recognized that some malignancies have specific cell-surface receptors that invite viral infection — but those proteins are also found to some degree in healthy cells, Dr Zamarin noted. Subsequent discoveries showed that these viruses also have other, diverse antitumor mechanisms of action. Some alter the tumor microenvironment, while others infect endothelial cells in a manner that can shut down tumor blood supply.

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And now, just over the past few years, Dr Zamarin and others have found evidence that oncolytic viruses don’t just kill cancer cells through infection and tumor cell destruction. They also bolster antitumor immune system attacks.1-7 That insight has inspired Dr Zamarin and his colleagues, and others, to explore investigational regimens that combine oncolytic viruses with immunotherapies like immune checkpoint inhibition.7-13 Dr Zamarin’s team was the first to demonstrate preclinical antitumor synergy between oncolytic Newcastle Disease Virus (NDV, injected directly into tumors) and systemic CTLA-4 checkpoint blockade.12 They also showed that PD-L1 in tumor microenvironments contributes to tumor resistance to oncolytic virus-triggered immune attack.13