New Haven, Conn. — The tissue adjacent to a tumor behaves differently than areas farther away: The tumor’s cancerous cells influence their surroundings, blocking the body’s immune defenses and creating a sort of haven in which the tumor can grow. Treatments that target some of these pro-tumor actions are effective in a number of cancers, but only for some patients; in others, these treatments have little effect.

Yale researchers have developed a new approach that simultaneously targets several of these pro-tumor actions at once, which they have demonstrated can effectively reduce tumor growth across several types of cancers.

Their new findings, published Jan. 16 in Nature Biotechnology, point to a potential new treatment that may benefit more patients than current therapeutic options.

“Traditional therapies target one molecule in the tumor microenvironment, but the microenvironment is so complex, targeting one thing doesn’t always work,” said Sidi Chen, an associate professor of genetics and neurosurgery at Yale School of Medicine and senior author of the study. “For example, the most well-known of these immunotherapies only benefits 20 to 30% of patients.”

When these therapies don’t work, it can be because the molecule they’re targeting doesn’t play a major role in the individual’s tumor or because there is some other molecule that has a similar effect and compensates for the loss of the one targeted by the treatment.

“Or it can be even more complex with say a large network of pathways within the tumor microenvironment all working to suppress the body’s immune response,” said Chen, who is also a researcher with the Systems Biology Institute at Yale’s West Campus. “So how do you hit multiple targets in the same go?”

For their approach, Chen and his colleagues used a gene editing molecule called Cas13, which targets and degrades RNA. (Its more widely discussed counterpart, known as Cas9, targets DNA.) One benefit of Cas13 is its ability to target multiple genes with one molecular package. So the researchers identified several genes that can suppress immune responses and developed a Cas13 system that targeted each of them.

When they delivered the Cas13 package into tumor microenvironments in mice, they found that it silenced those immune suppression genes (essentially un-silencing or re-activating the immune system), remodeled the microenvironment, and boosted antitumor immune responses. The result was reduced tumor growth across four types of cancers: breast cancer, melanoma, pancreatic cancer, and colon cancer.

While more research will be required to further optimize this approach for efficacy and safety, researchers say this technology holds promise as both an “off-the-shelf” treatment for more general use and one that can be tailored for specific individuals by swapping gene targets as necessary.

The researchers are continuing this line of research with the goal of working toward translation and clinical trials.

Coauthors Feifei Zhang, Guangchuan Wang, and Ryan Chow, all of Yale, led the research with Chen.
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