Researchers at City of Hope combine oncolytic virus with a CAR-T to eradicate solid tumors in mice
A new combination of existing cancer treatments is showing early signs of potentially cracking open a new approach to treating solid tumors.
In preclinical research published by City of Hope, a California-based non-profit, scientists effectively blended CAR-T therapy with an oncolytic virus to eradicate solid tumors in mice. The virus is genetically engineered to enter the tumors and force them to express the CD19 protein, allowing the CAR-T cells to attack.
“We came up with the idea based on the compatible expertise and essentially with several investigators at City of Hope,” Saul Priceman, senior author of the paper, told Endpoints News. “It was almost an idea to overcome the challenges associated with treating solid tumors with CAR-T cell therapy … the challenge being what tumor antigen to go after in solid tumors and also what we call the immunosuppressive microenvironment.”
The researchers are expecting to move into human trials within the next year and a half. Priceman added he likes to describe the method as “mark and kill,” where the virus marks the tumor with a recognizable target for the CAR-T cells that then go in for the kill.
Normally used to treat blood cancers like B cell lymphomas and acute lymphoblastic leukemia, CAR-T therapy has made significant headway since netting its first FDA approval back in late 2017. The success seen in these cancers hasn’t translated into solid tumors as of yet given that finding receptors on the surfaces of those cells is much more challenging and can lead to unwanted toxicities.
By combining CAR-T with a virus that essentially compels the tumors into expressing a receptor like CD19, however, Priceman hopes this concept can be a game-changer. Specifically in the mouse trials, Priceman and his team showed the virus was able to express CD19 in triple-negative breast cancer, as well as in pancreatic, prostate, ovarian, and head and neck cancer, as well as brain tumor cells.
Oncolytic viruses have had markedly less success when used on their own to treat cancers, according to paper co-author Anthony Park, largely because the immune system can develop a resistance. They’ve also never been tested clinically, but with CAR-T’s safety profile already well-known, the team is expecting positive results.
When used alone, the oncolytic virus “will induce an endogenous immune response, which could be beneficial for targeting tumors, but it can also be detrimental to the virus activity because the immune system can recognize the virus to not only show the tumor cells but also get rid of the virus,” Park said.
City of Hope’s results have already impressed some outside experts, namely Ezra Cohen, the chief of UC San Diego’s hematology-oncology division. Cohen, who himself is researching a similar combination using ROR1-targeting CAR-T cells, said City of Hope used a “clever approach” and found an added bonus in the study when the virus propagated into other tumor cells after the originally-infected cells died off.
That could suggest widespread efficacy even if the oncolytic virus doesn’t manage to infect every single tumor cell.
“You’ve got this hammer, which has been successful in hematological diseases, but you can’t use it for all the patients with solid tumors because you can’t see the nail,” Cohen said. “But what City of Hope did is they put the nail into cells that they wanted, and now all of a sudden you can use that hammer and it becomes effective.”
The biggest challenge moving forward will be how well the experiments in mice can translate into humans. Some experimental CAR-T therapies have failed at this stage before, Cohen said, as getting the treatment to hone in on the tumor when it’s not directly injected into its cells — something that’s not always possible in humans with metastatic cancers — is immensely difficult.
But Priceman is confident in the expertise of the City of Hope team, noting that the institution has 30 active Phase I clinical trials with CAR-T cells in a range of diseases.
“One of the beauties of City of Hope is we’ve done this a number of times,” Priceman said. “Clinical translation of a CAR-T cell is something we have a wide expertise in, and we’ve also growing expertise in oncolytic viruses.”
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