Double Blow: Scientists Find New Way to Combat Cancer
A drug compound developed by specialists at Johns Hopkins University, which blocks glutamine metabolism, is capable of slowing tumour growth, altering its microenvironment structure, and stimulating the production of resilient and highly active anti-tumour 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 tumour. 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 a wide variety of cancers, considering the enormous role of glutamine in stimulating the metabolism necessary for rapid tumour growth.
Their research, published in the scientific journal Science, revealed unexpected differences in the metabolic pathways feeding 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 tumour growth and alter 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 absolutely 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 pleases me about metabolic therapy is that treatments like ours become targeted, as they primarily affect the target cells.”
The experimental compound under the working name JHU083 was tested on mouse models of bowel cancer, lymphoma, and melanoma (aggressive skin cancer). “Initially, we thought that if we could influence the metabolism of the tumour, we would achieve two goals at once: slow down the growth of the neoplasm and change its microenvironment,” says Dr. Powell. “The tumour 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 tumour creates around itself is, in some sense, a direct result of its metabolism.”
As experiments showed, in mice with different types of cancer, treatment with the JHU083 compound led to a significant reduction in tumour growth and improved survival. This occurred due to the disruption of malignant cell metabolism and its influence on the tumour microenvironment. In some rodents, after treatment with just the experimental drug, there was a prolonged and sustained remission. Scientists believe that the main reason for recovery lies in the fact that metabolic therapy activated and enhanced the natural anti-tumour immune response.
When researchers reintroduced malignant cells to mice that had recovered from cancer, they found that none of them developed a new tumour. 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 inhibit the immune system's ability to destroy them.
“At first, we thought we would need to use both drugs sequentially to avoid any possible influence 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 tumour 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 tumour cells. They found some similarities, but mostly 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 that infiltrate the tumour, making them more resilient and viable in its microenvironment. “By blocking glutamine metabolism, we made these cells stronger, more like memory immune cells,” the team noted.
The scientists also demonstrated that using the JHU083 drug 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-tumour 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 "manual training" of 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 tumours can overcome the metabolic trap set by the drug. It is quite possible that tumours 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 tumours,” conclude the researchers.