Can targeting one metabolic signaling pathway have completely opposite effects on different subsets of T cells? In the case of glutamine metabolism, the answer seems to be “yes,” scientists at Vanderbilt University Medical Center recently uncovered. And they've figured out a way to potentially improve the cancer-fighting ability of engineered cell treatments known as CAR-Ts.
When an enzyme called glutaminase—which converts glutamine into glutamic acid—was inhibited, T cells that regulate anticancer responses became more active, while T cells that give rise to inflammatory and autoimmune diseases performed worse, the Vanderbilt team reported in the journal Cell.
“We were intrigued that one metabolic perturbation could have a very different impact on the function of subsets of T cells,” said Marc Johnson, a graduate student who led the studies, in a statement.
Glutamine is prevalent in the body, and as a kind of amino acid, it is essential for cell growth. However, it can also be abducted by cancer cells and become a driver for tumor progression. Previous studies have shown that many tumors are avid glutamine consumers, so inhibiting that process has become a strategy that scientists are exploring against cancer.
For their study, the Vanderbilt team used a glutaminase inhibitor from Calithera Biosciences. The drug, dubbed CD-839, is currently being tested in phase 2 studies in renal cell carcinoma and solid tumors. A group of researchers at New York University have previously found that mutated KEAP1 and KRAS genes may make lung cancer cells more vulnerable to CD-839, as the drug starved the tumor of glutamate.
To further examine the impact of glutaminase inhibition on T cells that mediate anti-cancer responses, the Vanderbilt team tested CD-839 in a mouse model of CAR-T therapy.
Before they started the trial, the investigators had expected that blocking glutamine metabolism would in general prevent T-cell function. Instead, they found that CD-839 improved CAR-T function, and the T cells lasted longer after exposure to the inhibitor.
“One of the problems with CAR-T cell therapy is survival of the engineered cells,” Johnson said. “We think that a short treatment with a glutaminase inhibitor might improve the persistence of CAR-T cells.”
The researchers believe their findings could also offer new way to enhance cancer immunotherapies such as checkpoint inhibitors. In fact, CD-839 is being tested alongside Bristol-Myers Squibb’s PD-1 inhibitor Opdivo in solid tumors. The investigators are now testing various dosing schedules in mouse models of cancer.
In addition, the researchers also found the inhibitor could be repurposed to treat inflammatory and autoimmune diseases, said Jeffrey Rathmell, a professor of immunobiology and a member of the team. In mouse models of allergic asthma, inflammatory bowel disease and chronic rejection of transplanted tissue, removing glutaminase actually reduced activity of T cells involved in these conditions, according to the team.