It revealed that glutamine blocking overcomes tumor immune evasion mechanism.

Introduction: whether jhu-083 is safe and effective in human remains to be further verified.glutamine is the most abundant free amino acid in human body.it is an important energy source for many immune cells and small intestinal mucosal epithelial cells, an important regulator of protein synthesis, and an important carrier of nitrogen and carbon in the body. It has a wide range of physiological functions.cancer cells are like greedy snakes. They ingest a large amount of molecules that are crucial for their survival and proliferation. However, this kind of voracious swallowing also turns their surrounding environment - tumor microenvironment - into acidic, hypoxic and nutrient deficient, which makes T cells infiltrating into the tumor microenvironment suffer from functional failure and cannot kill cancer cells.one of the nutrients many tumors need is glutamine.since the 1950s, people have been trying to exploit the dependence of tumor on glutamine to develop drugs to block glutamine metabolism.for example, a bacterial derived compound called don (6-diazo-5-oxo-L-norleucine) is a commonly used glutamine antagonist that kills tumors by inhibiting several enzymes that allow cancer cells to use glutamine.however, in clinical trials, the drug caused severe nausea and vomiting and was never approved.chemical structures of Don and jhu-083, a glutamine antagonist, are shown in translational oncology, 2019, doi:10.1016/j.tranon.2019.05.013 。to this end, Jonathan Powell, deputy director of the Institute of cancer immunotherapy, Kimmel Cancer Center, Johns Hopkins University, and his team prepared its precursor drug jhu-083 by adding chemical groups to Don and blocking its carboxyl and amino groups.after administration, when it reaches the tumor, the enzymes wandering around the tumor will remove these chemical groups, turn jhu-083 into don, and release don directly to cancer cells, which can delay tumor growth, change tumor microenvironment, and promote the production of persistent high activity anti-tumor T cells.the relevant research results were published online in science on November 7, 2019.previously, Brittany riggle et al. Found that jhu-083 can reverse brain edema, blood-brain barrier dysfunction and hemorrhage in mouse models of cerebral malaria, and pointed out that jhu-083 can be used as a potential adjuvant therapy for children and adults with fatal cerebral malaria.Allison hanaford et al. Found that jhu-083 can reduce the growth of cancer cells and promote cell apoptosis in cell and animal models, and has the potential to treat myc expressing neuroblastoma.however, the mechanism of jhu-083 remains to be further studied.now, Powell team has confirmed that in a variety of different mouse cancer models (colorectal cancer, lymphoma, and melanoma), blocking glutamine metabolism with jhu-083 can inhibit the oxidative and glycolytic metabolism of cancer cells, reverse hypoxia, acidosis and nutrient deficiency in tumor microenvironment, which makes T cells active in tumor microenvironment, instead of inhibiting glutamine metabolism There will be functional failure.furthermore, the response of effector T cells to glutamyl blockade is to significantly up regulate the oxidative metabolism, and show a long-lived, highly activated phenotype.this is the first time in the world that glutamine inhibitors have different effects on T cells and cancer cells, which is equivalent to "starving" tumor while "feeding" effector T cells.these different changes in cell metabolism form the basis for the treatment of cancer by producing a strong anti-tumor response.there is no doubt that the result of this drug treatment is a significant decrease in tumor growth and an increase in the survival rate of these mice.in many mice, treatment with jhu-083 alone resulted in a durable cure.this cure is due to the natural antitumor immune response activated by this metabolic therapy.when the new tumors were reinjected into the mice that had been successfully cured but did not have cancer, they found that almost all of the mice developed immune rejection against the new tumors, which indicated that jhu-083 treatment produced a strong immune memory, which could identify and attack new cancers.they also treated these mice with jhu-083 and anti PD-1 immune checkpoint inhibitors, a class of immunotherapeutic drugs that relieve cancer cells from inhibiting T cells.Powell said: "at first, we thought we needed to give these two drugs in turn to avoid any potential impact of metabolic therapy on immunotherapy.however, it is worth noting that this combination therapy works best when we give them at the same time."compared with using only anti-PD-1 immune checkpoint inhibitors, the combination of these two drugs can enhance their anti-tumor effect.given that jhu-083 has a very positive and direct effect on T cells, the Powell team explored the reasons for this.after blocking glutamine metabolism with jhu-083, Powell and his colleagues found that there were significant differences in the expression of metabolism related genes in tumor cells and effector T cells by analyzing and comparing the gene expression of tumor cells and effector T cells, which indicated that their metabolic pathways were very different.these differences may be used as "metabolic checkpoints" to evaluate tumor immunotherapy.in addition, given the urgent demand for glutamine in many tumors, this means that jhu-083 may be able to treat a wide range of cancer types.this also means that jhu-083 has the potential to become a broad-spectrum anticancer drug.however, although this study shows that cancer cells need glutamine more urgently than normal cells, jhu-083 selectively targets cancer cells, but glutamine metabolism is essential for almost all cells in the body. When using jhu-083 to treat cancer, how to kill cancer cells as much as possible and minimize the impact on normal cells Further research is needed. in addition, up to now, the experiments on jhu-083 have been carried out in cell and animal models, and no clinical trials have been carried out in humans. Therefore, whether jhu-083 is safe and effective in human remains to be further verified. after all, there have been many examples that drugs that are effective for mice are usually ineffective in humans, as is the case with Don. of course, if human clinical trials prove that jhu-083 is indeed safe and effective, it will have a bright future. this bright future is likely to begin next year, when Powell will conduct safety testing of the drug in humans. References: 1. Brittany rig et al, doi:10.1073/pnas.1812909115.2.Allison Hanaford et al. Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma. Translational Oncology, 2019, doi:10.1016/j.tranon.2019.05.013.3.  Robert D. Leone et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science, 2019, doi:10.1126/science.aav2588.4. 80% of professional doctors are using mace medical app to improve medical quality