Cancer Drug Restores Immune System’s Ability to Fight Tumors

A new, bio-inspired drug restores the effectiveness of immune cells in fighting cancer, a team led by researchers at The University of Texas at Austin has found. 

Many cancers delete a stretch of DNA called 9p21, which is the most common deletion across all cancers, occurring in 25%-50% of certain cancers such as melanoma, bladder cancer, mesothelioma and some brain cancers. Scientists have long known that cancers with the 9p21 deletion mean worse outcomes for patients and resistance to immunotherapies — the treatment strategies designed to supercharge a patient’s natural immune response to cancer.

The deletion helps cancer cells avoid getting detected and wiped out by the immune system, in part by prompting the cancer to pump out a toxic compound called MTA that impairs normal functioning of immune cells and also blocks the effectiveness of immunotherapies.

“In animal models, our drug lowers MTA back down to normal, and the immune system comes back on,” said Everett Stone who led the work. “We see a lot more T cells around the tumor, and they’re in attack mode. T cells are an important immune cell type, like a SWAT team that can recognize tumor cells and pump them full of enzymes that chew up the tumor from the inside out.”

The 9p21 deletion leads to the loss of some key genes in cancer cells. Gone are a pair of genes that produce cell cycle regulators — proteins that keep healthy cells growing and dividing at a slow, steady rate. When those genes are lost, cells can grow unchecked. That’s what makes them cancerous. Also deleted is a housekeeping gene that produces an enzyme that breaks down the toxin MTA. It’s this loss, according to Stone, that lets cancer cells acquire a new superpower: the ability to deactivate the immune system.

“Cancer gets a two-for-one when it loses both of these genes,” Stone said. “It loses the brakes that normally keep it from growing in an uncontrolled manner. And then at the same time, it disarms the body’s police force. So, it becomes a much more aggressive and malignant kind of cancer.”

To create their drug candidate, Stone and his colleagues started with the helpful enzyme that’s naturally produced by the body to break down MTA and then added flexible polymers.

“It’s already a really good enzyme, but we needed to optimize it to last longer in the body,” Stone said. “If we injected just the natural enzyme, it would be eliminated within a few hours. In mice, our modified version stays in circulation for days; in humans it will last even longer.”

The researchers plan to do more safety tests on their drug, called PEG-MTAP, and are seeking funding to take it into human clinical trials.

Sources:

Donjeta Gjuka, Elio Adib, Kendra Garrison, Jianfeng Chen, Yuxue Zhang, Wenjiao Li, Daniel Boutz, Candice Lamb, Yuri Tanno, Amin Nassar, Talal El Zarif, Neil Kale, Mehrdad Rakaee, Tarek H. Mouhieddine, Sarah Abou Alaiwi, Alexander Gusev, Thomas Rogers, Jianjun Gao, George Georgiou, David J. Kwiatkowski, Everett Stone. Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance. Cancer Cell, 2023; 41 (10): 1774 DOI: 10.1016/j.ccell.2023.09.005

University of Texas at Austin. “Cancer drug restores immune system’s ability to fight tumors.” ScienceDaily. ScienceDaily, 9 October 2023. <www.sciencedaily.com/releases/2023/10/231009191643.htm>.

Materials provided by University of Texas at Austin. Note: Content may be edited for style and length.

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Photo by National Cancer Institute

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