Science: glutamine blockers enhance antitumor response and are expected to be used in car-t cell therapy

November 10, 2019 / biogaky BIOON / - -- in a new study, researchers from Johns Hopkins University in the United States found that a compound that blocks glutamine metabolism can delay tumor growth, change tumor microenvironment, and promote the production of long-lasting and highly active anti-tumor T cells The relevant research results were published online in the journal Science on November 7, 2019 The title of the paper is "glutamine blockade causes diverse metallic programs to achieve more immune evaluation" The chemical structure of glutamine antagonist Don and its precursor drug jhu-083 The picture is from translational oncology, 2019, DOI: 10.1016/j.tranon.2019.05.013 As a "prodrug" of glutamine antagonist don, this compound produces its active form (i.e don) after enzymatic reaction in vivo and plays a role in tumor In theory, given the key role of glutamine in the metabolism needed to promote tumor crazy growth, this compound may be able to be used to treat a variety of cancer types, said Jonathan Powell, Ph.D., co-author of the paper and deputy director of cancer immunotherapy Research Institute at Kimmel Cancer Center, Johns Hopkins University Their study revealed surprising differences between cancer cells and effector T cells in the metabolic pathways that provide energy, previously thought to be very similar Powell said the differences could be used as a "metabolic checkpoint" for cancer treatment "By targeting glutamine metabolism, we can not only inhibit tumor growth and change tumor microenvironment, but also change T cells in a way that significantly enhances cancer immunotherapy," he said Powell said that although glutamine metabolism is necessary for all cells in the body, the Don precursor drug selectively targets tumor cells because of their most urgent need for glutamine "The new situation in metabolic therapy - which is why it's so exciting for me - is that treatments like ours are selective because they preferentially affect cancer cells that have the greatest need for glutamine." Powell and his colleagues tested a Don prodrug called jhu083 (also known as jhu-083) in mouse models of colon cancer, lymphoma and melanoma "At first, the idea was that if we could target tumor metabolism, then we could achieve two goals: delaying tumor growth and changing tumor microenvironment," Powell said Tumor microenvironment - cells, blood vessels, and nutrients in the vicinity of a tumor - can prevent immune responses because it is usually acidic, hypoxic, and nutrient deficient "In a sense, the immune barrier that a tumor creates around itself is a direct result of tumor metabolism," he said These researchers found that in a variety of different mouse cancer models, jhu083 treatment can significantly reduce tumor growth and improve survival rate by destroying tumor cell metabolism and its impact on tumor microenvironment In many mice, treatment with jhu083 alone can lead to a permanent cure This cure is due to the natural antitumor immune response activated by this metabolic therapy When these mice were injected with new tumors to cure cancer free mice, they found that almost all mice had immune rejection of the new tumors, which indicated that jhu083 treatment had a strong immune memory, so that they could recognize and attack new cancer They also treated these mice with jhu083 and anti-PD-1 immunosuppressive checkpoint inhibitors, a class of immunotherapeutic drugs that can relieve the inhibition of cancer cells on T cells "At first, we thought we needed to use the two drugs in turn to avoid any potential effects of metabolic therapy on immunotherapy," Powell said However, it is worth noting that this combination treatment has proved to work best when we give them at the same time " Compared with the use of only anti-PD-1 immunocheckpoint inhibitors, the use of both drugs can enhance their antitumor effect "We found that jhu083 has a very positive and direct effect on T cells, and we have to study the reasons for that," Powell said After analyzing and comparing gene expression in tumor cells treated and in immune cells called effector T cells, Powell and his colleagues noticed that there was a difference in gene expression related to metabolism between the two cells, which allowed them to guess how these T cells provide energy for themselves The researchers found some similarities, but fundamentally, the metabolic pathways of tumor cells and effector T cells are very different, and it is based on these differences that they conducted glutamine blocking drug treatment These differences enable effector T cells to respond to glutamine blockade by producing persistent and efficient tumor infiltrating T cells that appear to be active in the tumor microenvironment without failure "By blocking glutamine metabolism, we make these cells more persistent, more like an immune memory cell," Powell said The researchers also demonstrated that the use of jhu083 in the treatment of tumors can enhance the efficacy of adoptive cell therapy As an immunotherapy, adoptive cell therapy first collects T cells and proliferates them in the laboratory, then transplants them into patients to enhance their immune response to cancer These findings suggest that this new approach may also be used to enhance a promising class of adoptive cell therapies called car-t cell therapy In future studies, Powell and his colleagues want to study how jhu083 can be used in combination with different types of immunotherapy to explore whether some tumors can overcome the metabolic trap produced by jhu083 Potentially, tumors that produce metabolic pathways that avoid the effects of jhu083 may find themselves in a "dead end," Powell said "By adding other metabolic antagonists, it is also possible to remove drug-resistant tumors." (BIOON Com) reference: 1 Robert D Leone et al Glutamine blockade causes diverse metallic programs to achieve more immune evaluation Science, 2019, doi:10.1126/science.aav2588 2.Glutamine-blocking drug slows tumor growth and strengthens anti-tumor response https://medicalxpress.com/news/2019-11-glutamine-blocking-drug-tumor-growth-anti-tumor.html 3.Revamped cancer drug starves tumors in mice https://