A compound developed by Johns Hopkins researchers that blocks glutamine metabolism can slow tumor growth, alter tumor microen environment and promote the production of strong and highly active anti-tumor T cells .
The drug, a "prodrug" version of the glutamine antagonist DON, is designed so that the active form of the drug works within the tumor. In theory, this compound can be used in a broad spectrum of cancer types, says Jonathan Powell, MD, Ph.D., associate director of the Bloomberg ~ Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center, and colleagues due to the critical role of glutamine in promoting the metabolism necessary for fatigue tumor growth.
Their study, published online November 7 in Science revealed surprising variations in metabolic pathways that infiltrate cancer cells and effector T cells, pathways that previously thought to be similar. These variations can be taken advantage of as a "metabolic checkpoint" in treating cancer, Powell says.
"By targeting glutamine metabolism, we not only inhibit tumor growth and alter the tumor microenvironment, but also alter T cells in a way that we noticeably enhance immunotherapy for cancer, "he said.
Although glutamine metabolism is a component of all body cells, the DON prodrug selects targeted tumor cells because they are the "hungriest" for glutamine, Powell said. "What is emerging from metabolic therapy ̵1; and to me this is why it's so exciting – is that choices like ours are becoming more selective because they are more likely to affect cells with the most needs. . "
Powell and colleagues tested the DON prodrug, dubbed JHU083, in rat models of colon cancer, lymphoma and melanoma.
"At first, we thought that if we could target tumor metabolism, we would achieve two goals: slow tumor growth and change the tumor microenvironment," Powell says. The tumor microenvironment – the cells, blood vessels and nutrients around the tumors – is very hostile to the immune response because it is usually acidic, hypoxic and nutrient-depleted. "The immune shield created by the tumor around itself is in a sense a direct result of tumor metabolism," he says.
In mice, treatment with JHU083 led to a significant decrease in tumor growth and improved survival in many different cancer models. , by derailing tumor metabolism and its effects on the tumor microenvironment, the research team found. In a number of mice, treatment with JHU083 alone led to strong remedies. These remedies are simplified because metabolic therapy abolishes the natural immune-anti-tumor response. When researchers re-suggested these cancer-free mice with new tumors, they found that almost all mice rejected the new tumor, suggesting that treatment with JHU083 produced a strong immune memory to identify and attack the new cancer.
They also treated mice with JHU083 and an anti-PD-1 checkpoint inhibitor, a type of immunotherapy drug that removes suppressors in cancer cells that are placed on immune cells. "At first, we thought we would need to use these two sequences to avoid any potential impact of metabolic therapy on immunotherapy," Powell said. "Interestingly, however, it turned out that the combined treatment worked best when we gave them one at a time." Simultaneous treatment with drugs produced improved anti-tumor effects compared to anti-PD-1 therapy alone.
"We've found that JHU083 has a very positive, very direct effect on immune cells, and we need to investigate why." Powell said.
After examining and comparing gene expression in treated tumor cells and a type of immune cell called Tector cells, Powell and colleagues noted differences in gene expression associated with metabolism , allowing them to predict how the T cell will fuel itself compared to the tumor.
They found some similarities, but fundamentally the metabolic programming of tumor cells and the effector T immune cells was very different, and these are the differences researchers have taken advantage of by offering glutamine blocking drugs. .
Differences allow effector T cells to respond to glutamine blockade by producing long-term, effective effective T-infiltrating T cells that appear to be stronger in mice than they are in tumor microenvironment. "By blocking glutamine metabolism, we make these cells more patient, more like an immune memory cell," Powell said. where immune T cells are collected and grown in large numbers in the laboratory before being given to patients to boost the immune response against cancer. These findings suggest that this new approach could also be used to enhance a promising type of adoptive cell therapy called CAR-T. In future studies, Powell and colleagues want to examine how JHU083 is combined with different types of immunotherapy to discover if certain tumors can overcome the metabolic trap put in by JHU083. themselves in a "blind alley," Powell said. "By adding an additional metabolic antagonist, you can get rid of resistant tumors too."
The drug shows promise as immune therapy for cancer
Robert D. Leone et al, Glutamine block induces diverse metabolic programs to overcome immune suppression, Science (2019). DOI: 10.1126 / science.aav2588
Glutamine-blocking drug slows down tumor growth and stimulates anti-tumor response (2019, November 8)
acquired November 9, 2019
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