Gladstone Affiliate Investigator Kole Roybal conducts an experiment in a laboratory at UCSF

A new technique detailed in the journal Nature made human T-cells 100 times more potent at killing cancer cells; Kole Roybal, an affiliate investigator at Gladstone and member of the Gladstone-UCSF Institute of Genomic Immunology, conducted the research at UCSF in conjunction with collaborators at Northwestern Medicine. (Photo courtesy of UCSF)

 

Scientists may have found a way around the limitations of engineered T cells by borrowing a few tricks from cancer itself.

The research, which appears in Nature, was conducted at UC San Francisco and Northwestern Medicine, and was co-led by Gladstone Affiliate Investigator Kole Roybal, PhD—an 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-UCSF Institute of Genomic Immunology.

By studying mutations in malignant T cells that cause lymphoma, the team zeroed in on one that imparted exceptional potency to engineered T cells used for cancer therapy. Inserting a gene encoding this unique mutation into normal human T cells, which play a key role in the immune system, made them more than 100 times more potent at killing cancer cells without any signs of becoming toxic.

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.

“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,” says Roybal, co-senior author of the study.

“We used nature’s roadmap to make better T cell therapies,” says Jaehyuk Choi, MD PhD, an associate professor of Dermatology and of Biochemistry and Molecular Genetics at Northwestern University Feinberg School of Medicine, also a co-senior author. “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.”

A Solution Hiding in Plain Sight

Creating effective immunotherapies has proven difficult against most cancers because the tumor creates an environment focused on sustaining itself, redirecting resources like oxygen and nutrients for its own benefit. Often, tumors hijack the body’s immune system, causing it to defend the cancer, instead of attacking it.

Not only does this impair the ability of regular T cells to target cancer cells, it undermines the effectiveness of the engineered T cells that are used in immunotherapies, which quickly tire against the tumor’s defenses.

“For cell-based treatments to work under these conditions,” Roybal says, “we need to give healthy T cells abilities that are beyond what they can naturally achieve.”

The scientists 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 non-toxic, subjecting it to a rigorous set of safety tests.

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

Kole Roybal, PhD

“Our discoveries empower T cells to kill multiple cancer types,” says 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. 

“T cells have the potential to offer cures to people who are heavily pretreated and have a poor prognosis,” Choi says. “Cell therapies are living drugs, because they live and grow inside the patient and can provide long-term immunity against cancer.”

In collaboration with the Parker Institute for Cancer Immunotherapy and the venture capital firm 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 says. “There’s so much to learn from nature about how we can enhance these cells and tailor them to different types of diseases.”

This article was adapted from a Northwestern Medical press release.

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About the Study

The study, “Naturally Occurring T Cell Mutations Enhance Engineered T Cell Therapies,” appeared in the February 7, 2024 issue of Nature. The research was supported by the Parker Institute for Cancer Immunotherapy, NIH grants (grants F30 CA265107, T32 CA009560, 1DP2AI136599-01 and DP2 CA239143), Cancer Moonshot grant U54 CA244438, the Mark Foundation for Cancer Research, the Bakewell Foundation, and UCSF Helen Diller Family Comprehensive Cancer Center.

Co-senior authors Kole Roybal and Jaehyuk Choi are inventors on patents related to these discoveries and are co-founders and equity holders in Moonlight Bio.

About Gladstone Institutes

Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds.

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