Doctors have known for nearly a century that when cancer patients catch a virus the infection can help to beat back their tumors. But developing therapies hinged upon this idea has not been easy. Researchers first have to engineer the viruses to discriminately attack only the cancer cells. Then the virus has to actually reach those tumor cells and kill them. Despite these barriers, research has plunged forward, with several viruses in late-stage clinical development (see ‘Recent deal highlights hopes for cancer-killing viruses’).
Clinicians typically inject these so-called ‘oncolytic viruses’ into the tumors themselves using a syringe. But this delivery approach lacks precision. Thus, researchers have long sought cancer-killing viruses that can home in on cancerous cells on their own while leaving healthy tissue intact. (Scientists are similarly trying to develop bacteria that serve the same purpose, as we reported in March.) Now, for the first time, researchers have engineered a virus that, when injected into people’s bloodstreams, preferentially attacks only cancer cells.
“This data set really puts oncolytic virotherapy on the map as a very, very promising experimental approach to the systemic treatment of metastatic cancer,” Stephen Russell, director of the molecular medicine program at the Mayo Clinic in Rochester, Minnesota who was not involved with the research, wrote in an email.
In the new study, a team led by John Bell, a cancer researcher at Ottawa Hospital Research Institute in Canada, and David Kirn, president and CEO of San Francisco-based Jennerex Pharmaceuticals, engineered a poxvirus to target cancer cells and, once inside the tumor, activate the immune system as well as express a reporter gene. Their poxvirus, dubbed JX-594, can only replicate in the presence of thymidine kinase, an enzyme downstream of a growth signaling pathway often activated in tumors, so it leaves normal cells alone while proliferating inside cancer cells.
In a phase 1, proof-of-concept study, the researchers injected the modified virus into the bloodstreams of 23 people with a variety of metastatic cancers — lung, colon, skin, thyroid and ovarian, to name a few — and performed biopsies on cancerous and noncancerous tissue eight days later. Reporting today in Nature, the researchers found that those study subjects given lower doses of the treatment had no virus in their tumors. But seven of the eight participants given higher doses had viral particles in just the cancerous tissue, providing evidence that the virus gets to the tissue and only infects the cancer.
For their safety trial, Bell and his colleagues used fairly benign genes to prove that the virus made its way into the tumors. But in the future, the researchers plan to load up the vector with drug converting enzymes, immune stimulants or bacterial toxins to help kill off tumor cells. (Beyond its intravenous use, Jennerex is running randomized clinical trials testing tumor-injected JX-594 in people with liver cancer, too.)
“The exciting piece about it is that you can get a virus to go in there and to replicate and to produce as a gene-delivery vehicle,” says Timothy Cripe, co-medical director of clinical and translational research at Cincinnati’s Children’s Hospital, who was not involved in the study.
The seven patients that reacted to the virus did see their cancer stabilize — although it’s a little early to make any sweeping conclusions about its efficacy. “It’s a small trial with a small number of patients so I wouldn’t want to sell the bank on that data,” says Bell. “But it’s a hint that we’re seeing real biologic activity.”