Double Blow: Scientists Find New Way to Combat Cancer
A drug compound developed by specialists at the private research university Johns Hopkins, which blocks glutamine metabolism, is capable of slowing tumor growth, altering its microenvironment structure, and stimulating the production of resilient and highly active anti-tumor lymphocytes.
The drug, which is a "prodrug" version of the glutamine antagonist DON, is designed so that its active form is formed and begins to act directly within the tumor. According to Jonathan Powell, the head of the research team leading the Cancer Immunotherapy Institute at the Johns Hopkins University Hospital Cancer Center, theoretically this compound can be used to fight various types of cancer, considering the significant role of glutamine in stimulating the metabolism necessary for rapid tumor growth.
Their research, published in the scientific journal Science, revealed unexpected differences in the metabolic pathways fueling cancer cells and effector T cells, which were previously thought to be very similar. (Effector cells are immune cells that directly perform tasks specific to a particular type of lymphocyte: for example, detecting, recognizing, and destroying malignant cells). According to the scientists, these differences can be used as a "metabolic checkpoint" in cancer treatment.
“By affecting glutamine metabolism, we were able not only to suppress tumor growth and change its microenvironment but also to modify T cells to significantly enhance the effectiveness of cancer immunotherapy,” says Dr. Powell. And although glutamine metabolism is a component of all cells in the body, the scientist notes that the compound developed by his team selectively affects only cancer cells, as they need and consume glutamine much more than others: “What particularly excites me about metabolic therapy is that treatments like ours become targeted, as they predominantly affect the target cells.”
The experimental compound under the working name JHU083 was tested on mouse models of colorectal cancer, lymphoma, and melanoma (aggressive skin cancer). “Initially, we thought that if we could influence tumor metabolism, we would achieve two goals at once: slow the growth of the neoplasm and change its microenvironment,” says Dr. Powell. “The tumor microenvironment — the cells, blood vessels, and nutrients in close proximity to it — is very hostile to the immune response because it usually represents an acidic, hypoxic, and nutrient-deprived environment. This immune shield that the tumor creates around itself is, in a sense, a direct result of its metabolism.”
Experiments showed that in mice with different types of cancer, treatment with the JHU083 compound led to a significant reduction in tumor growth and improved survival. This occurred due to the disruption of malignant cell metabolism and its impact on the tumor microenvironment. In some rodents, after treatment with the experimental drug alone, there was a long-lasting and stable remission. Scientists believe that the main reason for recovery lies in the fact that metabolic therapy activated and enhanced the natural anti-tumor immune response.
When researchers reintroduced malignant cells to the cancer-free mice, they found that none of them developed a new tumor. They believe that treatment with JHU083 formed a strong immune memory in the animals, allowing the immune system to recognize and attack new cancer cells.
In another experiment, they treated rodents with the new compound in combination with a PD-1 protein inhibitor, a component of the "programmed cell death" system. This immunotherapeutic drug blocks the mechanisms by which cancer cells hinder the immune system's ability to destroy them.
“At first, we thought we would need to use both drugs sequentially to avoid any potential impact of metabolic therapy on immunotherapy,” explains Jonathan Powell. “But interestingly, it turned out that combination therapy worked better when we administered both drugs simultaneously.” It had a stronger effect on the tumor compared to therapy with just the PD-1 inhibitor. “We found that JHU083 has a positive, very direct effect on immune cells, and we decided to find out why,” says Powell.
By analyzing and comparing gene expression features in cancer cells treated with the drug and effector T cells of the immune system, researchers noticed differences in gene expression related to metabolism, which led them to think about differences in the nutrition of T cells and tumor cells. They found some similarities, but mainly the metabolic programming of malignant cells and immune system cells was completely different, and it was these differences that the scientists used in developing the glutamine-blocking drug.
These differences allowed effector T cells, in response to glutamine blockade, to produce resilient, highly effective lymphocytes infiltrating the tumor, which became more resilient and viable in its microenvironment. “By blocking glutamine metabolism, we made these cells stronger, more like memory immune cells,” the team noted.
Scientists also demonstrated that the use of JHU083 enhances the effectiveness of adoptive cell therapy — a type of immunotherapy where immune T cells are isolated from the patient's blood and grown in large quantities in the laboratory, after which they are returned to enhance the immune anti-tumor response. These results suggest that the new approach can also be used to enhance one of the most promising directions of adoptive therapy — CAR-T therapy, which involves "training" the patient's immune cells to fight cancer.
In future studies, Dr. Powell and his colleagues plan to investigate how JHU083 interacts with various types of immunotherapy to determine whether certain types of tumors can overcome the metabolic trap laid by the drug. It is quite possible that tumors that develop metabolic pathways to counteract the drug's effects may find themselves in a deadlock. “By adding another additional anti-metabolite, it may be possible to deal with resistant tumors,” conclude the researchers.