A compound developed by Johns Hopkins researchers that blocks glutamine metabolism may slow tumor growth, alter tumor microenvironment, and promote the production of durable and highly active antitumor T cells.
The drug, a "prodrug" version of the glutamine antagonist DON, is designed so that the active form of the drug functions within the tumor. In theory, this compound can be used in a wide variety of cancers, says Jonathan Powell, Ph.D., assistant professor, director of Bloomberg ~ Kimmel Cancer Immunotherapy Institute at Jones Hopkins Cancer Center and his colleagues because of the critical role of glutamine. to promote the metabolism required for tumor growth.
Their study, published online on November 7 in Science reveals surprising differences in the metabolic pathways that nourish cancer cells and effector T cells, pathways that were thought to be very similar. These differences can be used as a "metabolic checkpoint" in the treatment of cancer, Powell says.
"By focusing on glutamine metabolism, we not only succeeded in inhibiting tumor growth and altering the tumor microenvironment, but also altering T cells, thereby greatly improving cancer immunotherapy," he says.
Although glutamine metabolism is a component of all cells in the body, DON selectively selects tumor cells because they are "the most hungry" for glutamine, Powell said. "What comes up with metabolic therapy ̵
Powell and colleagues tested DON's prodrug called JHU083 in mouse models of colon cancer, lymphoma and melanoma.
"At the beginning, our thought was that if we could focus on the metabolism of the tumor, we could achieve two goals: slowing the growth of the tumor and changing the microenvironment of the tumor," says Powell, Tumor Microenvironment – Cells, Blood Vessels and nutrients close to the tumors – is very hostile to the immune response as it is usually acidic, hypoxic and depletes nutrients. "This immune shield that the tumor creates around itself is, in a sense, a direct result of tumor metabolism," he says.
In mice, treatment with JHU083 led to a significant reduction in tumor growth and improved survival in many different cancer models, by deranging tumor cell metabolism and its effects on the tumor microenvironment, the research team found. In many mice, treatment with JHU083 alone resulted in lasting treatments. These treatments were facilitated as metabolic therapy unleashed a natural antitumor immune response. When researchers re-injected these cancer-free mice with new tumors, they found that almost all mice rejected the new tumor, suggesting that JHU083 treatment created a powerful immune memory to recognize and attack the new cancer.
They also treated mice with JHU083 and a checkpoint anti-PD-1 inhibitor, a type of immunotherapy drug that eliminates restriction cancer cells, is placed on immune cells. "Initially, we thought we would have to use both therapies sequentially to avoid the potential impact of metabolic therapy on immunotherapy," Powell says. "However, it is noteworthy that combination therapy has proven to work best when given at the same time."
"We found that JHU083 had a very positive, very direct effect on immune cells and we had to investigate why," Powell said.
After analyzing and comparing gene expression in treated tumor cells and an immune cell type called effector T cells, Powell, and colleagues noted differences in gene expression associated with metabolism, allowing them to speculate how T
found some similarities, but basically the metabolic programming of tumor cells and T cell effector immune cells was completely different, and this are these spills Researchers used glutamine-blocking drug
Differences allow effector T cells to respond to glutamine blocking by producing long-lasting, highly effective tumor-infiltrating T cells that appear to be invigorated in rats rather than depleted in rats. "By blocking the metabolism of glutamine, we made these cells more resistant, more like cells from immune memory," Powell notes.
The group also demonstrated that the treatment of tumors with JHU083 enhances the efficacy of host cell therapy, a type of immunotherapy in which immune T cells are harvested and grown in large numbers in the laboratory before being given to patients to increase the immune response against cancer. These findings suggest that this new approach can also be used to improve a promising type of adoptive cell therapy called CAR-T. In future studies, Powell and colleagues want to explore how JHU083 is combined with different types of immunotherapy to examine whether certain tumors can overcome the metabolic trap posed by JHU083.
Potentially tumors that develop metabolic pathways can avoid the effects of JHU083 themselves in a "blind alley", Powell said. "By adding an additional metabolic antagonist, you could potentially get rid of resistant tumors as well."
The drug shows promise as an immune therapy for cancer
Robert D. Leone et al., Glutamine Blockade Causes Different Metabolic Programs to Overcome Immune Tumor Evasion, Science (2019). Doi: 10.1126 / science.aav2588
Glutamine blocking drug slows down tumor growth and boosts antitumor response (2019, November 8)
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