SC Connecticut News

Yale researchers have uncovered a way to make a type of white blood cell known as natural killer cells— which kill infected, damaged, or malignant cells in the body—more effective against cancer. The approach, they say, could enable new treatments for solid tumors in the future.

The findings were published June 25 in Nature Biotechnology.

CAR-T cell therapy is a treatment that was approved by the U.S. Food and Drug Administration in 2017 that boosts the cancer-killing ability of immune cells called T cells. For the therapy, T cells are taken from a patient’s blood, genetically modified to better recognize cancer cells, and returned to the patient.

While this therapy has been effective for treating blood cancers and offers another option for patients who’ve had little success with other treatments, it has downsides.

“It can be very toxic,” said Sidi Chen, associate professor of genetics at Yale School of Medicine and senior author of the new study. “Many patients experience severe side effects of CAR-T such as cytokine release syndrome, which can make them very sick or even kill them.”

CAR-T cell therapy is also patient-specific in that a patient’s own T cells have to be used.

But a novel treatment known as CAR-NK therapy, which uses natural killer cells rather than T cells, is now undergoing clinical trials and it addresses some of CAR-T cell therapy’s shortcomings. It’s similarly effective, much safer, and can be made with donor natural killer cells, meaning it can be “off the shelf” and used in many patients rather than made specifically for each individual.

“But the limitation is that CAR-NK cells cannot efficiently get into solid tumors like breast or colorectal tumors,” said Chen, who is also a member of Yale Systems Biology Institute on Yale West Campus and the Yale Cancer Center. “They’re not effective against them.”

Cellular checkpoints are genes that prevent a cell from becoming overly active. They’re essentially the cell’s brakes," said Chen. For the new study, researchers led by Lei Peng—a postdoctoral fellow in Chen’s lab and first author of the study—set out to find natural killer cell checkpoints that could be targeted to boost their activity in tumors. In other words, they wanted to find these brakes and turn them off to see if that might help infiltrate solid tumors.

They did this by knocking out—or deactivating—thousands of genes in natural killer cells; putting those mutant cells into mice with four different types of tumors (melanoma, breast cancer, glioblastoma, and pancreatic cancer); and identifying which mutants were able to infiltrate and accumulate in these tumors. Several mutants were able to do so; revealing several checkpoints that might serve as targets to improve CAR-NK therapy.

Following experiments including genetic screening and single-cell profiling; researchers honed in on one checkpoint: CALHM2. They then knocked out CALHM2 in natural killer cells observing how these behaved within tumor environments.

“We found that knocking out CALHM2 made natural killer cells more potent regarding cancer-killing; more efficient at infiltrating tumors; producing anti-tumor cytokines (proteins key for immune system signaling),” said Chen. “And this was true across multiple cancer types.”

Knocking out CALHM2 also made CAR-NK therapy effective against colorectal tumors within animal models accordingto researchers' findings.

“When we introduced typical CAR-NK therapy into colorectal tumor—it did nothing,” said Chen.” But when we appliedthe same without CALHM2—the results were miraculous showingCALHM2is indeed targetable."

Researchers reintroducedCALHM2into previously knocked-outcells reducingtheiranti-cancer activity provingthat higher gene presence suppressed activities.Thisoppositeapproachcould modeltreatingautoimmunityreducingharmfulcellactivitysaidChen

Going forwardChenandhislabworktowardsclarifyingwhyCALHM2hastheeffectitdoesandtakingstepsforclinicaltrials

“Wealso wanttoextendapplicabilityofthisapproachtoevenmorediseasemodels”saidChen

Paul RenauerapostdoctoralfellowatYaleCancerCenterisco-firstauthorofthestudy.ChenandformerlabmemberLupengYearecorrespondingauthors.The researchwasprimarilyfundedbytheNationalInstitutesofHealthandtheU.S.DepartmentofDefense.