CAR-T cell therapies such as Gilead Sciences’ Yescarta and Novartis’ Kymriah have been proven useful against B-cell blood cancers, but the technology has been difficult to translate to solid tumors. Now scientists at the La Jolla Institute for Immunology have pinpointed proteins that contribute to that deficiency, a discovery that they believe could lead to better immuno-oncology therapies.
CAR-T treatments involve genetically engineering a patient’s own T cells to be able to mount an immune attack on cancer cells, and then infusing them back into the body. The immune system maintains a balance between immune response and immune tolerance, but that balance can tip toward the latter when T cells are exposed to chronic infection or the tumor microenvironment—a phenomenon known as "T cell exhaustion." The exact molecular mechanism of T cell exhaustion has been a mystery, but scientists believe it partially explains why CAR-Ts can't act on solid tumors.
Now the LJI researchers have found a way to rejuvenate exhausted T cells, and it involves a family of proteins called Nr4a transcription factors. When they gave CAR-Ts that lack all three Nr4a proteins to mice, their tumors began to shrink and they lived longer. The scientists reported their findings in the journal Nature.
The team, led by LJI researcher Anjana Rao, Ph.D., previously observed increased levels of Nr4a in T cells that fight chronic viral infections. Over time, those T cells seemed to grow tolerant to the viral antigens and stopped working. The Rao lab also found that another family of proteins called NFAT turned on Nr4a in T cells that entered tumors, suggesting that both proteins were somehow involved in wearing out cancer-fighting T cells.
Building on those findings, Rao and colleagues tested their theory in CAR-T cells. They modified some cells to lack the three Nr4a proteins. In tumor-bearing mouse models, the experimental CAR-T cells promoted tumor regression and kept most of the mice alive over the 90-day study period, while the rodents that got normal CAR-Ts died of cancer by day 35, according to the team. Moreover, the modified CAR-Ts showed greater anti-tumor activity than did similar cells that were only lacking one Nr4a protein.
CAR-T is still a relatively new class of cancer treatment, and scientists are working to improve upon the first generation of treatments. A team at Boston University recently created a split, universal and programmable CAR system that allows scientists to control the strength of T-cell activation to either avoid dangerous side effects or combat relapse. The team is working with Senti Biosciences on translating the technology into human studies.
Joyce Chen, the first author of the La Jolla study, says her team's research could open the door to addressing T-cell exhaustion in future CAR-T therapies. Identifying NFAT and Nr4a offers cancer researchers potential new targets for improving CAR-Ts, she says in a statement.
However, Chen admits there is much more work to be done. For example, the researchers need to understand the safety consequences of editing multiple genes in human cells. Chen says future research could investigate the role of other transcription factors in T cell exhaustion, especially those that are found along the NFAT and Nr4a signaling pathway.