Scientists are exploring various methods to enable CAR-T cell therapy to treat solid tumors. A research team at Mayo Clinic has now proposed loading engineered CAR-T cells with cancer-killing viruses as a promising approach.
Vesicular stomatitis virus (VSV) or reovirus could enhance the antitumor capabilities of CAR-T cells that carry the viruses as cargo, scientists at Mayo Clinic described in a new study published in Science Translational Medicines.
Such combinations of CAR-T cells and oncolytic viruses helped mice with melanoma and brain tumors live longer than mice that received the CAR-T cells alone. Another booster shot of the same virus led to even longer antitumor benefit, the team found.
The findings show that systemic delivery of CAR-T cell therapy paired with an oncolytic virus warrant further development, the Mayo Clinic team said. The reovirus used in the study came from Oncolytics Biotech. The Canadian company is developing a reovirus candidate called pelareorep in combination with various agents in cancer, with HR-positive, HER2-negative breast cancer its most advanced clinical program.
CAR-T cell therapy has revolutionized treatment for certain blood cancers, but its use in solid tumors has been hampered. This is partly because the tumor microenvironment can be difficult for CAR-T cells to penetrate and survive. To overcome the challenge, the Mayo Clinic team originally tried pretreating mice with oncolytic viruses, but the immune response induced that way caused death among the following CAR-T cells.
The team then turned to a co-administration approach. The method could enable systemic delivery, expand CAR-T cells by stimulating their native T-cell receptors against viral antigens, and trigger other changes to further enhance the cells’ antitumor potency, the researchers argue.
“This approach allows the tumor to be killed by the virus as well as by the CAR-T cells,” Richard Vile, Ph.D., the study’s corresponding author, said in a statement. “In addition, when the virus is delivered, it turns the tumor into a very inflammatory environment, which the patient’s own immune system then sees and starts to attack.”
The researchers tested the approach in mice with EGFRvIII-expressing melanoma tumors. EGFRvIII-directed mouse CAR-T cells preloaded with VSV prolonged the lives of mice compared to either unloaded CAR-T cells or the virus alone, the team reported.
Despite the improvement, the virus-loaded CAR-T cells couldn’t continuously contain the cancer over the long term. But the cells appeared to have adopted an immune memory against the tumor. A booster shot of VSV—not a different virus—restimulated the CAR-T cells and protected six of seven mice against tumor for up to 60 days.
The researchers observed similar results when adding Oncolytics Biotech’s reovirus to the CAR-T cells. What’s more, this strategy of preloading with reovirus and subsequent boosting with the same virus also cured over 80% of mice of aggressive EGFRvIII brain tumors, “indicating that this strategy is not dependent on the location of the tumor being treated,” the researchers wrote in the study.
Oncolytic viruses have been developed as immunotherapy against cancer because they can kill the tumor cells directly or act like a vaccine to trigger an immune response. Plus, some viruses can be genetically engineered to carry toxic payloads or force the tumor to express certain antigens. Amgen’s Imlygic is an HSV-1 virus engineered to express GM-CSF, and it’s FDA-approved to treat melanoma.
The idea of combining oncolytic virus and CAR-T therapy is already on many research groups’ radar. PsiOxus and bluebird bio—now through its oncology-focused spinoff 2seventy bio—have designed a vector based on the oncolytic adenovirus enadenotucirev to encode human immunomodulatory molecules. The pair previously showed the viral vector could enhance EGFR CAR-T cells in a mouse model of lung cancer.
City of Hope recently out-licensed a CD19-expressing oncolytic virus to Australian biotech Imugene for further development alongside CD19-targeted CAR-T therapy. Solid tumors don’t express CD19, but the oncolytic virus created at City of Hope, called onCARlytics, forces its expression on the tumors, opening up the cancer cells for targeting by CAR-T therapy.
By comparison, a therapy that loads CAR-T cells with oncolytic viruses might face regulatory hurdles because it would technically be two products, Vile and colleagues at Mayo Clinic said in their study. But on the upside, many cancer patients have now already been treated with CAR-T cells and oncolytic virus therapies separately.
This new strategy also holds an advantage in that it doesn’t require lymphodepletion, the team noted. For existing CAR-T products, patients need to undergo days of lympho-depleting chemotherapy to allow sufficient engraftment of the new CAR-T cells. And being able to deliver the therapy systemically represents another advantage over other approaches that require injection into the tumor because it would allow for treating patients with metastatic disease, Vile said.