Tumor with green patches of vaccinia virus infection surrounded by red blood vessels. Image courtesy Donald McDonald.
A new UC San Francisco study has shown that a cancer-killing (“oncolytic”) virus currently in clinical trials may function as a cancer vaccine — in addition to killing some cancer cells directly, the virus alerts the immune system to the presence of a tumor, triggering a powerful, widespread immune response that kills cancer cells far outside the virus-infected region.
Using novel approaches to examine exactly how oncolytic viruses attack tumors, the new study — published online in early form on December 19, 2017, and in print in the February 15, 2018, issue of Cancer Research — provided surprising insights about how a viral infection can cooperate with the immune system to attack cancer cells. The study highlights an opportunity to combine this form of therapy with cancer immunotherapy drugs such as checkpoint inhibitors, which unleash the immune system’s full cancer-fighting power, the researchers say.
The idea that viruses could fight cancer goes back to the early 20th century, when doctors noted that cancer patients sometimes experienced dramatic remission after getting viral infections. Researchers have been developing oncolytic viruses since the 1980s, but following the U.S. Food and Drug Administration’s 2015 approval of Amgen’s Imlygic (T-Vec) as the first oncolytic viral therapy in the U.S., such viruses have become a closely watched area of therapeutic development.
However, researchers are still trying to understand the fundamentals of how viral therapies actually kill cancer cells, and how to optimize their effects. In different contexts, viruses appear capable of attacking tumors in a number of different ways — by directly infecting them, by releasing tumor proteins that trigger a broad immune response against the cancer, and by damaging the blood supply tumors need to survive.
To better understand the underlying mechanisms of these viral therapies, a collaboration was forged between UCSF vascular researcher Donald McDonald, MD, PhD, and researchers at San Francisco-based biotech SillaJen Biotherapeutics Inc. (formerly Jennerex Biotherapeutics, Inc.), a subsidiary of SillaJen, Inc., headquartered in Korea.
SillaJen is developing an oncolytic viral therapy called Pexa-Vec, currently in phase III and phase Ib/II clinical trials for use against primary liver and colorectal cancers, respectively. Pexa-Vec is an engineered virus based on the harmless vaccinia cowpox virus — also the basis for the original smallpox vaccine. Early observations suggesting that the virus might attack cancer in part by damaging blood vessels that feed tumor growth led the SillaJen team to strike up a collaboration with McDonald, an expert in tumor vasculature, to investigate the virus’s mechanism of action in animal models.
“This got my attention in part because this virus could be given systemically by intravenous injection, in contrast to most oncolytic viruses that are injected into the tumor itself, which obviously limits their therapeutic potential against cancers that are inaccessible or have spread to multiple sites in the body,” said McDonald, who is a member of the UCSF Helen Diller Family Comprehensive Cancer Center and the Cardiovascular Research Institute at UCSF.