UCLA scientists have found a way to feed cancer-fighting immune cells with a fuel that tumors cannot steal. The strategy could help next-generation CAR-T and other T cell therapies work better against tough solid tumors.
For years, one of the biggest frustrations in cancer immunotherapy has been watching powerful immune cells falter as they enter solid tumors and run out of energy. Now, UCLA researchers say they have found a way to keep those cells fueled with a sugar that tumors cannot touch.
In preclinical studies, the team engineered T cells, including CAR-T cells, to tap into an alternative energy source and stay active in the harsh, low-nutrient environment inside solid tumors. The work, published in the journal Cell, points to a potential new way to make immunotherapies more effective against cancers such as lung, breast and colorectal tumors.
Solid tumors are notorious for outcompeting immune cells for nutrients. Cancer cells consume glucose at a high rate, creating a microenvironment where even aggressive T cells become functionally exhausted and, in effect, starved of fuel.
Senior author 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, explained that nutrient tug-of-war.
“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,” he said in a news release. “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 get around that problem, the UCLA team looked for a fuel that T cells could use but tumor cells could not. They landed on cellobiose, a naturally occurring sugar that comes from plant fiber, or cellulose. Cellobiose is considered safe by the U.S. Food and Drug Administration and is already added to products such as infant formula, drinks, candies and icings.
Human cells, including cancer cells, cannot normally break down cellobiose. But some microbes and fungi can. The researchers borrowed that microbial trick.
By equipping T cells with two proteins derived from fungi, they enabled the immune cells to import cellobiose and convert it into glucose inside the cell. In other words, the T cells gained a private fuel line that tumors could not tap.
The team first tested these engineered T cells in laboratory systems designed to mimic the nutrient-poor conditions inside solid tumors, where glucose levels can drop to a fraction of what is found in healthy tissues. Under those stressful conditions, unmodified T cells quickly lost function. They stopped dividing, produced fewer cancer-fighting signaling molecules called cytokines, and became less effective at killing tumor cells.
The modified T cells told a different story. Fed with cellobiose, they stayed alive, continued to proliferate, produced key cytokines such as interferon gamma and tumor necrosis factor, and maintained their tumor-killing ability even when external glucose was scarce.
“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,” added first author Matthew Miller, a former doctoral student in Butte’s lab and now a postdoctoral fellow at the Salk Institute.
Next, the researchers moved into mouse models of solid cancer. Mice received tumor-targeted T cells that had been engineered to metabolize cellobiose, along with access to the sugar. Compared with animals treated with standard T cells, those given the modified cells showed slower tumor growth and lived significantly longer. In some cases, tumors regressed completely.
When the team examined immune cells inside the tumors, they found that the engineered T cells were more active and proliferated more, with fewer signs of exhaustion — a dysfunctional state that often limits immune responses in cancer.
The strategy also showed promise when applied to human CAR-T cells, a form of engineered T cell therapy already used to treat certain blood cancers like leukemias and lymphomas. CAR-T therapies have struggled in solid tumors in part because of the harsh metabolic environment.
In low-glucose lab conditions similar to those inside solid tumors, standard CAR-T cells lost viability and stopped producing cytokines. But when CAR-T cells were given access to cellobiose and engineered to use it, their survival, proliferation, cytokine production and tumor-killing ability were restored. In mouse models, these modified CAR-T cells were more active inside tumors and showed a strong trend toward better tumor control.
Butte noted the way the engineered cells behaved under extreme nutrient stress was a key signal that the idea could translate.
“The survival of T cells in minimal levels of glucose was a huge hint that this was going to work,” he 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.”
Beyond the specific experiments, the researchers see broad implications. Around the world, more than 500 clinical trials are testing CAR-T cells against solid tumors, and many of those efforts run into the same roadblocks of T cell exhaustion and failure in the tumor microenvironment.
Because the UCLA strategy involves adding just two genes and supplying a sugar that is already widely used in food products, the team believes it could be layered onto many existing T cell therapies.
“Our method has the potential to benefit virtually any T cell-based therapy being developed for solid tumors,” Butte added. “That’s what’s most exciting, the broad applicability. We can help a lot of efforts that are already underway.”
The work is still at the preclinical stage, and more research is needed before the approach can be tested in people. Future studies will likely focus on safety, optimal dosing and delivery of cellobiose, and how best to integrate the metabolic upgrade into different T cell therapies.
If those steps go well, the concept of giving immune cells their own protected fuel source could become a powerful new tool in the push to make immunotherapy work for more patients with solid tumors — not just in blood cancers, but in some of the most common and deadly cancers worldwide.
Source: UCLA Health