Understanding the mechanisms that drive cancer’s growth and identifying vulnerabilities particular to cancer cells are necessary for combating it. Scientists at UC San Francisco (UCSF) and Northwestern Medicine may have discovered a way to overcome the limits of modified T cells by stealing a few techniques from cancer itself.
They identified a mutation in malignant T cells that caused lymphoma that gave modified T cells remarkable potency. Inserting a gene expressing this particular mutation into normal human T cells increased their ability to kill cancer cells by more than 100 times without 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, lungs, and stomach in mice. The team has already begun working toward testing this new approach in people.
Our discoveries empower T cells to kill multiple cancer types. This approach performs better than anything we’ve seen before.
Dr. Jaehyuk Choi
“We used nature’s roadmap to make better T-cell therapies,” said Dr. Jaehyuk Choi, an associate professor of dermatology and of 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, 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 study will appear in Nature.
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, but it also 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 said, “we need to give healthy T cells abilities that are beyond what they can naturally achieve.”
The Northwestern and UCSF teams examined 71 mutations seen in T cell lymphoma patients and determined which ones could improve tailored T cell therapy in mice tumor models. Eventually, they isolated one that was both potent and non-toxic and subjected it to a battery of safety tests.
“Our discoveries empower T cells to kill multiple cancer types,” said Choi, a researcher at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center. “This approach performs better than anything we’ve seen before.” According to the scientists, their discovery can be used to treat a variety of cancers.
“T cells have the potential to offer cures to people who are heavily pretreated and have a poor prognosis,” he said. “Cell therapies are living drugs because they live and grow inside the patient and can provide long-term immunity against cancer.”
Roybal and Choi are forming a new firm, Moonlight Bio, in conjunction with the Parker Institute for Cancer Immunotherapy and Venrock, to realize the full potential of their breakthrough method. They are now developing a cancer therapy, which they expect to test in humans within the next several years.
