Scientists Unlock the Secret to Supercharged Cancer-Fighting T Cells

Researchers have revolutionized cancer immunotherapy by developing a way to grow T cells in the lab that live longer and fight cancer more effectively.

They identified flaws in traditional methods, where sugar-rich growth media caused T cells to depend on glucose and die quickly when reintroduced into the body. By supplementing the growth medium with dichloroacetate (DCA), the researchers improved the cells’ metabolism and durability, achieving better outcomes in mouse models of melanoma, with long-lasting immune protection against cancer.

A Breakthrough in Growing T Cells

Scientists at the University of Pittsburgh have developed an innovative method to grow T cells in the lab, allowing them to survive longer and more effectively attack cancer cells in a mouse model of melanoma compared to T cells grown using traditional methods.

Published today (January 28) in Cell Metabolism, this breakthrough has the potential to significantly enhance cancer immunotherapies, where T cells are extracted from a patient, expanded in large numbers in the lab, and then reinfused into the body to fight cancer.

“The way we traditionally grow T cells in the lab is horribly inefficient,” explained senior author Dr. Greg Delgoffe, professor in the Department of Immunology at Pitt’s School of Medicine and director of the Tumor Microenvironment Center at UPMC Hillman Cancer Center. “We make millions of T cells and we infuse them back into a patient, but most of the cells die. Our research is uncovering new ways to manufacture T cells that live for a long time with the goal of making cell therapies more effective.”

Enhancing Immunotherapy Effectiveness

Cell therapy is a type of treatment that involves removing immune cells from the patient, expanding them in a dish, and transferring these living cells back into the patient. Common forms of cell therapy that use T cells—the immune system’s soldiers that fight infections and cancers—include chimeric antigen receptor T cell (CAR-T), which are T cells modified to better target cancer, and tumor infiltrating lymphocyte (TIL) therapy, which uses naturally occurring T cells that can fight the tumor.

“Cell therapy is a living drug that responds to the environment in the body,” said lead author Andrew Frisch, graduate student in the Department of Immunology at Pitt’s School of Medicine. “But there is a major gap between where we are with these therapies and where we could be because the way we feed these cells in the lab does not prepare them well for surviving in the body.”

The Role of Glucose Addiction in T Cell Longevity

According to Delgoffe, traditional growth media is very high in glucose, so T cells grown in the lab become addicted to this sugar. When reinfused into a patient, they struggle to consume other energy sources and most of the transferred cells quickly die.

With the goal of growing longer-lasting T cells, Delgoffe, Frisch and their team supplemented a compound called dichloroacetate (DCA) to the typical growth medium used to expand T cells. DCA alters the metabolism of T cells

so they are less reliant on glucose and better able to use other energy sources more common in the bloodstream.

Promising Results in Melanoma Treatment

When infused into mice, T cells grown with DCA lived much longer compared to those grown in traditional culture media. Almost one year later, over 5% of circulating killer T cells were those that had been transferred. In comparison, in mice that received T cells grown in media lacking DCA, the researchers could barely detect these cells even a few weeks later. In animals with melanoma, treatment with the DCA-grown T cells led to better tumor control and survival than with traditionally grown cells. They also provided long-lasting protection: animals that received the DCA-grown T cells fought off a second challenge with melanoma cells.

Nourishing T Cells for Long-Term Impact

“By limiting the access to certain foods, we endowed immune cells with the ability to metabolize things that they would normally metabolize in the body, rather than getting them addicted to the sugar that we were feeding them in the lab,” said Delgoffe. “If we can properly nourish our T cell soldiers in the lab by convincing them to eat the right kind of food, they are better prepared to respond to signals in the body and live much longer. We might be able to have a soldier on guard forever. Just as after getting the chicken pox vaccine, you are protected for life – you’ll never get chicken pox again. That’s the ultimate goal of cell therapies for cancer.”

Reference: “Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy” by Andrew T. Frisch, Yiyang Wang, Bingxian Xie, Aaron Yang, B. Rhodes Ford, Supriya Joshi, Katarzyna M. Kedziora, Ronal Peralta, Drew Wilfahrt, Steven J. Mullett, Kellie Spahr, Konstantinos Lontos, Jessica A. Jana, Victoria G. Dean, William G. Gunn, Stacy Gelhaus, Amanda C. Poholek, Dayana B. Rivadeneira and Greg M. Delgoffe, 28 January 2025, Cell Metabolism.
DOI: 10.1016/j.cmet.2024.12.007

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