The Wonderful Power of CAR CAR-T therapy is the star of cancer immunotherapy. How to make it safer and more suitable for more cancer types? This is the direction that scientists have been working hard. Recently, scientists have found—CARs (chimeric antigen receptor)-mediated signal intensity will affect the T cell response, and this detail is expected to provide new clues for the development of the next generation of CAR-T. As a "living" drug, CAR-T therapy is very different from traditional drugs. First, the therapy needs to isolate T cells from the patient and modify them in vitro using a chimeric antigen receptor (CAR) to specifically recognize cancer cells, and finally expand and revert the engineered T cells to the patient. Although CAR-T therapy has shown great potential in blood cancer, scientists have so far failed to fully understand the biological pathways of CAR-T cells against cancer. They believe that understanding these pathways is important for the development of next-generation CAR-T cell therapies, which are expected to reduce side effects, prevent recurrence, and be used in solid tumor treatment. On August 21st, the journal ScienceSignaling published a study titled “Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function.” Scientists from the FredHutchinson Cancer Research Center designed two different CARs and compared their effects on T cells. They found that signal strength is a key factor in determining the fate of T cells. Stanley Riddell, author of the article and director of the Center for Integrated Immunotherapy, said: "When we started the study in 2014, we tried to understand the biological principles of CAR-T therapy." "CAR" The chimeric antigen receptor "car" is a synthetic receptor that modifies T cells. The part located on the surface of T cells is responsible for recognizing cancer cells, while the part located inside T cells is composed of different parts, including T cell signal units—a costimulatory domain. In the latest study, Stanley Riddell led the team to compare the differences between the two most common co-stimulatory domains, CD28 and 4-1BB. Specifically, they analyzed the details of the effects of these two different "cars" driving T cells on T cell behavior and against the effectiveness of human cancer cells. They found that both types of CARs initiate the same signaling pathway, but the signal time and intensity are different: 1) CD28 exhibits faster, stronger signal activity, while 4-1BB is relatively slower and milder.
Subsequently, the researchers demonstrated in mice with lymphoma that T cells modified with 41BB were more effective in clearing cancer cells. 2) A signaling protein, Lck, in T cells regulates the signal intensity of the CD28 CAR-T panel. This means that scientists can manipulate the protein to control the response of CD28. 3) 4-1BB CAR-T cells express more genes associated with T cell memory. This suggests that the 41BB CAR signal may help to prolong T cell life and maintain its anticancer effect. Compared with CAR-T cells with lower signal intensity (middle column), CAR-T cells with stronger signal intensity (right column, red) have weaker effects on mouse lymphoma cells. Significance Alex Salter, the first author of the article and MD, said: "People are very interested in T cells targeting cancer cells, but little is known about the indication of T cells by CARs. We hope to find out how CARs deliver instructions to T cells. ." “The results suggest that different CARs have different uses. The faster, stronger response of CD28 may be potent for some cancers, while the slower but more persistent 4-1BB may be effective for other cancers,� explains Alex Salter. Through mass spectrometry, the team conducted a comprehensive analysis of the proteins involved in T cell signaling. "We hope to develop a targeted assay for phosphorylated proteins in T cell signaling to advance the development of immunotherapy and develop more effective CAR-T cell therapy for patients," said Stanley Riddell. The researchers stressed that their findings do not mean that a certain CAR is better than others, but can explain why some patients cannot benefit from CAR-T therapy that is effective for other patients, and why some patients show serious side effects, and why some patients will relapse after treatment... Next, the Fred Hutch team will continue to explore how to design the next generation of "CARS". Collected by Creative BioMart.