Since scientists first discovered that human immune cells could be modified to become cancer-fighting agents, they’ve been trying to engineer a cell that’s effective against solid tumors, which account for the vast majority of cancer cases.
Yale scientists have engineered natural killer cells that eliminate solid tumors in mouse models. The study may lead to a simpler, “off the shelf” immunotherapy for hard-to-treat cancers. AI-generated image created by Sidi Chen / Yale University
In a key advance toward meeting this “holy grail challenge” in cancer cell therapy, a team of Yale scientists led by geneticist Sidi Chen has revealed how immune cells can be “boosted” to target and eradicate solid tumors.
The research was published in the journal Nature.
The field of cell therapy began to revolutionize cancer treatment several decades ago, when researchers pioneered the use of therapeutic cells. In this process, immune cells are removed from a patient, modified so that they can better fight cancer, and then reintroduced into the patient’s body.
Two major streams of this therapy exist: CAR–NK cell therapy, which uses a patient’s natural killer (NK) cells, and CAR-T cell therapy, which uses a patient’s T cells. In both cases, scientists genetically modify the cells to express Chimeric Antigen Receptor (CAR), a synthetic receptor that helps immune cells recognize proteins on cancer cells.
But while CAR therapies have been successful in treating blood cancers, they’re largely ineffective against solid tumors. Among other obstacles, these therapies struggle with poor infiltration into tumors and immune exhaustion.
In the new study, researchers discovered that adding a gene called OR7A10 to natural killer (CAR–NK) cells dramatically improved their ability to fight solid tumors. In multiple mouse model studies — targeting breast, colon, and ovarian cancers — the engineered cells showed far stronger tumor control than standard CAR–NK cells. In one breast cancer model, 100% of treated mice experienced complete tumor elimination.
“All of a sudden these NK cells started to work against solid tumors,” said Chen, an associate professor of genetics and neurosurgery at Yale School of Medicine (YSM). “We really believe this type of therapy has immense potential in patients.”
Ongoing research is now expanding to target brain and thyroid cancers, and Chen said he is hoping to start human trials in the next few years.
The study, which included a team of 20 researchers, spanned more than five years. “The work involved a lot of people, their efforts and creativity,” said co-senior author Lei Peng, an associate research scientist in neurosurgery at YSM. “We achieved a very good result and had a very enjoyable, collaborative lab culture.”
In their work, the research team first had to systematically identify which genes in NK cells would improve tumor control in mice. Among the tens of thousands scanned, OR7A10 emerged as the strongest candidate.
They then validated the finding by adding OR7A10 genes to human NK cells and testing these engineered cells against several types of cancer cells, measuring tumor killing ability, cytokine production, exhaustion markers, metabolic activity, and resistance to immunosuppressive conditions.
Across the experiments, OR7A10 consistently enhanced NK cell function and improved tumor control in multiple solid tumor models, the researchers said.
One major benefit of the potential new therapy, Chen said, is that CAR–NK cells can be safer, and readily, and less expensively, manufactured as an “off-the-shelf” treatment from donor cells, making them potentially faster and easier to deploy.
“We are not going to change the manufacturing process in future clinical studies,” he said. “This type of product is simple and clean, and it has the potential to democratize treatment and make it available to more patients in need.”
In addition to being a member of the Systems Biology Institute on Yale’s West Campus, Chen is also an affiliate of the Yale Cancer Center.
Source: Yale University