FDA-approved CAR-T cell therapies like Novartis’ Kymriah, target CD19, an antigen that’s widely expressed in some blood cancers. But these therapies aren’t useful for treating solid tumors, most of which express such a wide variety of proteins that they lack one clear target. What’s more, solid tumors create an environment that’s so hostile it’s difficult for CAR-T cells to survive, expand and fight the cancer.
City of Hope scientists say they’ve come up with a potential strategy for making CD19-targeted CAR-T cells work in solid tumors—and it involves a cancer-killing or “oncolytic” virus.
The City of Hope team engineered an oncolytic virus so it would produce a truncated version of CD19 in solid tumor cells. Their idea was that the antigen would travel to the surface of the tumor cells, making them targetable with CD19-directed CAR-T cell therapies. The combination worked in human cancer cells and mouse models, they reported in the journal Science Translational Medicine.
First, the researchers tried the combination in cells from several solid tumor types, including pancreatic, prostate and ovarian cancer. They found that the virus caused cancer cells to express CD19 long before they could be killed by the virus itself. That created a long enough time window for the CAR-T cells to get to work. The result: widespread killing of cancer cells.
The researchers went on to try the strategy in mouse tumor models. They found that combining the virus with CAR-T cells cured more than half the mice, while only 22% of mice that received the virus alone saw a complete regression of their tumors.
The researchers also discovered that in the animals that received the combination treatment, the virus continued to spread to cancer cells, causing “significantly greater tumor cell killing activity,” they wrote in the study. What’s more, when they re-challenged the cured mice with cancer cells, new tumors did not grow, suggesting that the virus-CAR-T combo created tumor-specific immune memory that protected the animals from cancer recurrence.
Viruses have long been of interest in the oncology research community because of their natural tendency to kill cancer. There is one oncolytic virus on the market, Amgen’s melanoma drug Imlygic, which is a modified form of the herpes virus. Several other viruses are in development, many of which are being tested as part of immunotherapy combination strategies.
In a study earlier this year led by Astellas, researchers used an engineered vaccinia virus particle to deliver the cytokines interleukin-7 (IL-7) and IL-12 into tumors in mice, creating an inflammatory environment that inhibited tumor growth. Combining the virus with drugs that blocked the immune checkpoints CTLA-4 and PD-1 was even more effective at stopping the growth of colorectal tumors in mice.
In the new study, the City of Hope researchers noted that half of the mice didn’t respond to the combination of the oncolytic virus and CAR-T cells, possibly because the treatments induced the checkpoint protein PD-L1. They suggested that combining the virus and CAR-T cells with a checkpoint-blocking drug could be a potential strategy to explore in future studies.
Co-author Saul Priceman, assistant professor of hematology and hematopoietic stem cell transplantation at City of Hope, believes the combination of CAR-T cells with the virus that induces CD19 in solid tumors could help cell therapy reach a wider group of patients. “One of the most exciting prospects of this study is that we may be able to use this or a variation of this for any patient with cancer,” Priceman said in a video.
The researchers are planning clinical trials, first to test the safety of their oncolytic virus in people and then to try the combination. They hope to start the trials in 2022.