Although CAR-T cell therapy has brought revolutionary progress to the field of cancer treatment, especially in the treatment of certain B-cell blood cancers such as leukemia, lymphoma and multiple myeloma, this therapy still faces a major challenge: many patients will eventually relapse even after a short period of complete remission.
In response to this problem, the research team of Dana-Farber Cancer Institute recently announced an innovative solution. They developed a new treatment platform called CAR enhancer (CAR-E), which aims to enhance the activity and persistence of CAR-T cells to avoid cancer recurrence. The relevant research results were published online in the journal Nature Biotechnology in July 2024, with the title "A CAR enhancer increases the activity and persistence of CAR T cells".
The uniqueness of the CAR-E therapeutic platform lies in its ability to stimulate CAR-T cells to remain active, prolong their survival time in the patient's body, and ensure that they can continue to fight until tumor cells are completely eliminated. In addition, CAR-E can also prompt CAR-T cells to form a memory of cancer cells. Once the cancer relapses, these memory cells can be quickly reactivated and put into battle again. In laboratory experiments on patient-derived cancer cell lines, CAR-E treatment has been shown to completely eliminate tumor cells, paving the way for the clinical application of this therapy in human patients.
Figure 1. CAR-E treatment results in enhanced persistence of CAR T cells in vivo. (Rakhshandehroo T, et al., 2024)
"Although CAR-T cell therapy has made breakthroughs in the treatment of B-cell blood cancers, almost all patients will eventually relapse, especially in the treatment of multiple myeloma." Dr. Mohammad Rashidian, the corresponding author of the paper and Dana-Farber Cancer Institute, said, "The challenge we face is how to keep CAR-T cells active and persistent for a longer time in the body. To this end, we have adopted a new strategy instead of simply modifying the CAR-T cells themselves."
Rashidian and his team developed a unique "platform" tool that can stimulate CAR-T cells from the outside, extend their lifespan and promote the formation of memory cells. This tool is a fusion molecule that contains a weakened form of the immune signaling molecule interleukin-2 (IL-2), as well as a specific antigen recognized by CAR-T cells. This weakened form of IL-2 has little effect on normal T cells, but when it binds to antigens and acts specifically on CAR-T cells, it can significantly activate and proliferate these cells.
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The research team found that CAR-E therapy not only promotes the proliferation of CAR-T cells, but also diversifies them to produce various types of memory T cells, including stem cell-like memory T cells, central memory T cells, and effector memory T cells. These cells are essential for building a comprehensive immune response to cancer. In laboratory cultures of myeloma cells and animal models, CAR-E therapy successfully achieved complete elimination of tumor cells. And the long-acting CAR-T cells produced can be reactivated by subsequent CAR-E treatment, providing new treatment opportunities for relapsed patients.
Not only that, CAR-E therapy may also simplify the process of CAR-T cell therapy, reduce the number of CAR-T cells required, reduce treatment costs, shorten patient waiting time, and reduce side effects such as cytokine release syndrome.
One of the most common side effects of CAR-T cell therapy is cytokine release syndrome, an overly aggressive immune response that causes fever, nausea, rapid heartbeat, neurological problems or other problems. With CAR-E, it is possible to skip the CAR-T cell expansion process entirely: just generate CAR-T cells and export them back to the patient, and then treat with CAR-E.
Researcher Rashidian said, "In animal experiments, we infused mice with very small numbers of CAR-T cells, and found that they could not clear the cancer. When we gave them CAR-E treatment, CAR-T cells were able to expand rapidly and clear the cancer." This shows that even a small number of CAR-T cells can successfully clear cancer with the help of CAR-E.
Currently, the research team is planning to launch the first clinical trial of CAR-E therapy, with the primary goal of ensuring safety and determining the optimal dose and timing of administration. The researchers are full of expectations for the prospects of CAR-E therapy and believe that it will bring major improvements to CAR-T cell therapy and provide patients with more effective cancer treatment options.
Reference
Rakhshandehroo T, et al. A CAR enhancer increases the activity and persistence of CAR T cells. Nature Biotechnology, 2024: 1-12.