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CAR-T cell therapies such as Yescarta from Gilead Sciences and Kymriah from Novartis have proven effective against B-cell blood cancers, but the technology is proving difficult to translate into solid tumors. Scientists at the La Jolla Institute of Immunology have identified proteins that contribute to this deficiency, a finding that they believe could lead to better immuno-oncological therapies.
CAR-T treatments involve the genetic engineering of the patient's T cells to enable them to attack the cancer cells in an immune manner and then reinject them back into the body. The immune system maintains a balance between immune response and immune tolerance, but this balance may shift to the latter when T cells are exposed to chronic infection or the tumor microenvironment – a phenomenon known as "T-cell depletion ". The exact molecular mechanism of T-cell depletion is a mystery, but scientists believe that it partly explains why CAR-Ts can not act on solid tumors.
Now, IJJ researchers have found a way to rejuvenate depleted T cells, and this is a family of proteins called Nr4a transcription factors. When they pass on the three missing Nr4a proteins to the mice, their tumors begin to contract and they have lived longer. The scientists reported their findings in the journal Nature.
The team, led by researcher LJI Anjana Rao, Ph.D., had previously observed an increase in Nr4a levels in T cells that fight chronic viral infections. Over time, these T cells seemed to become tolerant of viral antigens and stopped working. The Rao laboratory also discovered that another family of proteins called NFAT was activating Nr4a in T cells that entered tumors, suggesting that both proteins were somehow involved in the wear of T cells fighting against the cancer.
Building on these findings, Rao and his colleagues tested their theory in CAR-T cells. They have modified some cells so that they lack the three Nr4a proteins. On tumor-bearing mouse models, experimental CAR-T cells favored tumor regression and kept most mice alive during the 90-day study period, while rodents obtained a CAR-Ts normal died of cancer by day 35, according to the report. team. In addition, modified CAR-Ts had superior antitumor activity than similar cells that lacked only one Nr4a protein.
RELATED: CAR-T 2.0? A shared, universal and programmable system
CAR-T is still a relatively new class of cancer treatment, and scientists are working to improve the first generation of treatments. A team from Boston University recently created a dual, universal, programmable CAR system that allows scientists to control the strength of T-cell activation to avoid dangerous side effects or relapse. The team collaborates with Senti Biosciences in translating technology into human studies.
Joyce Chen, the first author of the La Jolla study, says that his team's research could open the door to solving the problem of T-cell depletion in future CAR-T therapies. Identifying NFAT and Nr4a offers cancer researchers new potential targets for improving T CARs, she said in a statement.
However, Chen admits that there is still a lot of work to be done. For example, researchers need to understand the safety implications of modifying multiple genes in human cells. According to Chen, future research could investigate the role of other transcription factors in T-cell depletion, particularly those found along the NFAT and Nr4a signaling pathways.
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