Scientists at the University of California, San Francisco (UCSF), and Northwestern Medicine have developed a new technique by using cancer’s tricks against itself. By studying mutations in malignant T cells that cause lymphoma, they zeroed in on one that imparted exceptional potency to engineered T cells. Inserting a gene encoding this unique mutation into normal human T cells made them more than 100 times more potent at killing cancer cells without any signs of becoming toxic.

Their findings are published in Nature in an article titled, “Naturally occurring T cell mutations enhance engineered T-cell therapies.”

While current immunotherapies work only against cancers of the blood and bone marrow, the T cells engineered by Northwestern and UCSF were able to kill tumors derived from skin, lung, and stomach in mice. The team has already begun working toward testing this new approach in people.

“Adoptive T-cell therapies have produced exceptional responses in a subset of patients with cancer,” the researchers wrote. “However, therapeutic efficacy can be hindered by poor T cell persistence and function. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we reasoned that these mutations could be co-opted to improve T-cell therapies. Here we systematically screened the effects of 71 mutations from T cell neoplasms on T-cell signaling, cytokine production, and in vivo persistence in tumors.”

“We used nature’s roadmap to make better T-cell therapies,” said Jaehyuk Choi, MD, PhD, an associate professor of dermatology and biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine. “The superpower that makes cancer cells so strong can be transferred into T-cell therapies to make them powerful enough to eliminate what were once incurable cancers.”

“Mutations underlying the resilience and adaptability of cancer cells can super-charge T cells to survive and thrive in the harsh conditions that tumors create,” said Kole Roybal, PhD, associate professor of microbiology and immunology at UCSF, center director for the Parker Institute for Cancer Immunotherapy Center at UCSF, and a member of the Gladstone Institute of Genomic Immunology.

The Northwestern and UCSF teams screened 71 mutations found in patients with T cell lymphoma and identified which ones could enhance engineered T-cell therapies in mouse tumor models. Eventually, they isolated one that proved both potent and nontoxic, subjecting it to a rigorous set of safety tests.

“Our discoveries empower T cells to kill multiple cancer types,” said Choi, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “This approach performs better than anything we’ve seen before.” Their discoveries can be incorporated into treatments for many types of cancer, the scientists said.

In collaboration with the Parker Institute for Cancer Immunotherapy and Venrock, Roybal and Choi are building a new company, Moonlight Bio, to realize the potential of their groundbreaking approach. They are currently developing a cancer therapy that they hope to begin testing in people within the next few years.

“We see this as the starting point,” Roybal said. “There’s so much to learn from nature about how we can enhance these cells and tailor them to different types of diseases.”

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