2 potential boosters for improving checkpoint inhibition in cancer

Syringe
A generic drug that improves blood flow and a modified form of the cowpox virus that's injected directly into tumors each show promise in enhancing checkpoint-inhibiting cancer drugs.

One of the biggest success stories in immuno-oncology in recent years is the rise of checkpoint inhibitors: drugs that inhibit proteins that would normally prevent immune cells from recognizing and attacking cancer. But for reasons that are still not well understood, checkpoint inhibitors do not work in the majority of patients. Only 20% of melanoma patients, for example, are cured by the drugs. That has prompted researchers to search for companion treatments that might boost the effectiveness of checkpoint inhibitors.

One potential booster, discovered by scientists at Columbia University Medical Center, in a drug that’s already on the market: pentoxifylline, which is used to increase blood flow in patients with poor circulation. The key to pentoxifylline’s activity in cancer is in a protein called c-Rel and its effect on certain immune cells known as regulatory T cells (Tregs).

Large populations of Tregs are found in several types of tumors. This is a problem, because Tregs seem to suppress the activity of the killer T cells that are so essential for destroying cancer. Yet destroying Tregs isn’t an option, because that could cause dangerous autoimmune reactions. So the Columbia researchers tried removing c-Rel from Tregs to see if that might change their function without sparking autoimmunity, according to a press release.

Pentoxifylline inhibits c-Rel, and in mouse models of melanoma, combining the drug with checkpoint inhibitors improved the effectiveness of the immunotherapies. The tumor burden in animals who received both drugs was lower than it was in mice who received checkpoint inhibitors alone. The research was published in the journal Cell.

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A research team at Memorial Sloan Kettering Cancer Center in New York is pursuing a different tactic for improving checkpoint inhibitors, combining them instead with a modified form of vaccinia—the virus that causes cowpox. They presented their results at the Third International Cancer Immunotherapy Conference in Germany.

They tested an inactivated form of modified vaccinia virus Ankara (MVA) by injecting it directly into the tumors of mice that were also given checkpoint inhibitors. They found that the combination helped generate two types of tumor-fighting T cells, according to a press release.

The idea behind the combination was to try to solve a problem that causes some patients to be resistant to checkpoint inhibition, said Liang Deng, a dermatologist at Memorial Sloan Kettering: Some tumors don’t have enough cancer-killing immune cells in them to be able to launch an effective attack. Injecting microbes into the tumors—in this case, cowpox—might prompt the immune system to recognize cancer as a foreign invader and send killer T cells to destroy it, they surmised. “Therefore, it is important to develop potent microbial-based agents to ‘light the fire’ in the tumor microenvironment,” Deng said in the release.

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Cancer-killing viruses, known as oncolytic viruses, are already being used in oncology. Amgen’s Imlygic, approved to treat some melanoma patients, is an engineered form of the herpes virus. As a solo treatment it has not been widely effective, but Amgen has partnered with Merck to test the virus along with the checkpoint inhibitor Keytruda.

The Columbia researchers interested in using pentoxifylline as an immunotherapy booster plan to test the combo in human clinical trials. Deng and her colleagues at Memorial Sloan Kettering plan to further investigate their virus-based therapies in human trials, as well.