Recently, in a research report titled "Metabolic priming of GD2 TRAC-CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence" published in the international journal Molecular Therapy-Methods & Clinical Development, scientists from the University of Wisconsin-Madison and other institutions have developed a new way to fight human cancer by studying T cells. Researchers said that this new therapy for treating blood cancer by using the power of the immune system to target and destroy cancer cells may be effective in treating human solid tumors.
In the article, researchers said that by changing the growth of T cells, it may be possible to improve the efficacy of chimeric antigen receptor T cell therapy (CAR-T cell therapy). T cells are a type of immune cell that is very important for fighting infection and cancer. They can be modified by CRISPR/Cas9 genome editing technology to express special receptors, thereby redirecting the natural "killer instinct" to target cancer cells. T cells can remember pathogens after the first contact with them, and if they encounter the same pathogen again, they will initiate a faster and stronger response, just like vaccines train the body's immune system to recognize and resist specific pathogens.
"But for these cells to be used as a powerful cancer therapy, they must be produced under specific conditions in the laboratory. We compared two different culture medium formulations for T cells grown under different nutritional conditions," said Cappabianca. "What we achieved was completely accidental. I accidentally put the cells in the wrong culture medium, which unexpectedly became the focus of the entire research paper."
Figure 1. Manufacturing TRAC-CAR T cells at clinically relevant scales. (Cappabianca D, et al., 2024)
In the body, T cells are derived from stem cells in the bone marrow. In the lab, the researchers activated the T cells in a nutrient-poor medium. The medium contained low concentrations of glucose and glutamine, which the cells need to grow, and then the researchers transferred the cells to a high-nutrient medium. The first step stresses the cells and induces specific processes that enhance their ability to target tumors and promote the formation of T memory cells, while also selecting for more plastic cells that can survive such low levels of energy. The second step supports the rapid growth and proliferation of T cells.
As a result of this "metabolic priming," the treated cells retain their stem cell-like properties, which enhances their ability to kill cancer cells, and can transform into long-lasting memory cells that can survive longer in the body. The researchers noted that by briefly limiting access to glucose (similar to a three-day ketogenic diet), the T cells showed less maturity at the end of the manufacturing process. When they were reinfused into the patient, they were less mature and could fight cancer longer. These two steps seem to help the cells remember. In CAR-T cell therapy, enhancing these memory properties may help T cells better recognize and fight cancer over time.
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In recent studies, researchers used T cells cultured in a new laboratory method. The results showed that 63% of patients experienced partial or complete tumor shrinkage over a period of time, which may be an improvement compared to clinical trials using CAR-T cells. CAR-T cells are not grown through a two-step process in the laboratory, and only 15% of patients experience partial or complete tumor shrinkage after treatment.
Later researchers also need to conduct in-depth research to understand the key factors that help these CAR-T cells survive longer and fight solid tumors more effectively. In the future, researchers hope that this process of "metabolic priming" of these specific types of CAR-T cells can be adapted to large-scale production, aiming to treat patients in the next few years.
Reference
Cappabianca D, et al. Metabolic priming of GD2 TRAC-CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence. Molecular Therapy Methods & Clinical Development, 2024, 32(2).