Researchers at UCLA have found a way to supercharge immune cells with a fuel source that tumors can’t steal, dramatically improving their ability to survive and attack solid tumors in preclinical studies.
The approach , published in the journal Cell , could help overcome a major barrier that has limited the effectiveness of CAR-T and other immunotherapies in solid tumors such as lung, breast and colorectal cancer, where immune cells are often “starved” of energy by aggressive cancer cells.
“A problem with solid tumors is that the immune system tries to fight the cancer, but the tumor cells deplete the key nutrient glucose from their environment,” said senior author Dr. Manish Butte , UCLA’s E. Richard Stiehm Professor of Pediatric Allergy, Immunology and Rheumatology and a member of the UCLA Health Jonsson Comprehensive Cancer Center . “This leaves the T cells that show up to attack with not enough glucose to make cytokines and kill. The balance between tumor cells eating the glucose and the T cells not having enough glucose is a key reason why tumors spread and elude immune attack.”
To overcome this metabolic roadblock, the team developed a method to feed T cells glucose without offering the glucose to the tumor. To do this, they turned to cellobiose, a naturally occurring sugar found in plant fiber (cellulose) that is non-toxic and generally regarded as safe by the U.S. Food and Drug Administration. It is routinely added to many foods, including infant formula, drinks, candies and icings. Human cells and tumors cannot break down cellobiose. But some microbes and fungi can.
By equipping T cells with two proteins derived from fungi, the researchers enabled the immune cells to import cellobiose and convert it into usable glucose inside the cell. In laboratory experiments designed to mimic the nutrient-poor tumor environment, where glucose levels can fall to a fraction of the levels of healthy tissues, these engineered T cells stayed alive, continued dividing, produced cancer-fighting cytokines such as IFN-γ and TNF, and effectively killed tumor cells, while unmodified T cells rapidly lost function.
The team then tested the strategy in mouse models of solid cancer. Mice treated with tumor-targeted T cells capable of metabolizing cellobiose showed slower tumor growth and lived significantly longer than those receiving standard immune cells. Some experienced complete tumor regression.
When researchers examined immune cells inside the tumors, they found that the engineered T cells were more active and proliferative and showed fewer signs of exhaustion, a state that limits immune responses in many cancers.
“We demonstrate not only that glucose can be a limiting component of an effective anti-tumor response, but that we can design strategies to bypass the metabolic tug-of-war and deliver a high-value nutrient to T cells engineered with the proprietary metabolic processing system,” said first author of the study Dr. Matthew Miller, a former doctoral student in Dr. Butte’s lab and now a postdoctoral fellow at the Salk Institute.
The approach also showed promise for human CAR-T cells, which are already used for certain leukemias and lymphomas. In low-glucose laboratory conditions similar to those found in solid tumors, levels that caused standard CAR-T cells to lose viability and cytokine production, cellobiose restored CAR-T cell survival, proliferation, cytokine production and tumor-killing ability. In mouse models, CAR-T cells given access to cellobiose were more active inside tumors and showed a strong trend toward improved tumor control.
“The survival of T cells in minimal levels of glucose was a huge hint that this was going to work,” Butte said. “We saw that when glucose was scarce, the modified T cells used cellobiose to power all the same core energy pathways they normally use glucose for. Their metabolism looked healthy and normal, not starved. Overall, the results demonstrate that providing immune cells with an exclusive, tumor-resistant fuel source enhances their metabolic fitness and anti-tumor activity in solid tumors.”
The approach could have broad implications, the researchers noted. There are currently more than 500 clinical trials worldwide testing CAR-T cells in solid tumors, many of which struggle with immune cell exhaustion and failure. The researchers believe adding these two genes, along with controlled delivery of cellobiose, could help many of those therapies succeed.
“Our method has the potential to benefit virtually any T cell-based therapy being developed for solid tumors,” Butte said. “That’s what’s most exciting, the broad applicability. We can help a lot of efforts that are already underway.”
Other authors, all from UCLA, are Timothy Thauland, Smriti Nagarajan, Wenqi Ellen Zuo and Miguel Moreno Lastre.
The work was supported in part by grants from the National Institutes of Health, the E. Richard Stiehm Endowment, the Natasha and Brandon Beck Foundation, the UCLA Jonsson Comprehensive Cancer Center Fellowship and the National Institutes of Health Ruth L. Kirschstein National Research Service Award.
Cell