Researchers at the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center (MECCC) have found that a revolutionary treatment for blood cancers can be modified to target solid tumors, which has the potential to revolutionize cancer treatment. The encouraging results involve CAR-T cell therapy, which boosts the immune system to recognize and destroy cancer cells.In an article published in Science Advances, research focuses on CAR-T cell therapy, a treatment that enhances the immune system’s ability to detect and eliminate cancer cells. According to Xingxing Zang, Ph.D., the senior author of the paper, while CAR-T cell therapy has transformed the treatment of blood cancers like leukemia and lymphoma, it has not been as effective in treating solid tumors. The study found that modifications to the standard CAR-T cell therapy can notably improve its effectiveness against solid tumors, including deadly pancreatic cancer and glioblastomas. Dr. Zang is a member of the MECCC Cancer Therapeutics Research Program and a professor of microbiology & immunology.Louis Goldstein Swan Chair in Cancer Research and the founding director of MECCC’s Institute for Immunotherapy of Cancer at Albert Einstein College of Medicine. Christopher Nishimura, an M.D./Ph.D. student in Dr. Zang’s lab, is the first author of the paper.
The researchers, led by Dr. Zang, developed five CAR-T therapies and tested them on mice with various types of solid human tumors. One of the therapies, which included two new components, showed promising results in safely and effectively reducing the size of glioblastoma and other tumors.
and tumors in the pancreas as well as tumors in the lungs.
CAR-T cell therapy, also known as chimeric antigen receptor (CAR)-T cell therapy, is a remarkable feat of genetic engineering that transforms T cells (a type of immune cell) into cancer-seeking missiles programmed to attack upon contact. The treatment involves taking the patient’s own T cells and giving them a single gene that encodes for multiple different proteins. (“Chimeric” comes from the Chimera of Greek mythology with its lion’s head, goat’s body, and serpent’s tail.) The genetically modified T cells are allowed to multiply and are then reintroduced into the patient.
Their specialSpecially created gene allows T cells to produce synthetic CAR receptors on their surface. These CARs can recognize specific proteins, called antigens, on cancer cells. This allows the T cells to target and attack cancer cells. Dr. Zang and his team successfully modified two of the four key proteins in CARs to effectively combat solid tumors.
Five CAR-Ts Confront Three Types of Cancer
All five CAR-T therapies developed by the Zang team used the same unique targeting protein: a monoclonal abeen attached, said Dr. Zang. In their study, the researchers used a costimulatory protein called 4-1BB to enhance the activity of the CAR-T cells. The team also found that the CAR-T cells were effective at killing the tumor cells and blood vessels in mouse models of human cancer without causing major side effects. This research shows that CAR-T cells can be engineered to target B7-H3 and effectively destroy solid tumors and their blood vessels, providing a potential new treatment option for cancer patients.Dr. Zang’s lab has been working on five different CAR-T cell therapies, four of which utilized costimulatory proteins that were already in use. However, their fifth therapy used a new protein that had never been used in CAR-T cell therapy before. In 2015, Dr. Zang discovered a receptor called TMIGD2 in T cells, which activates the cells when stimulated. He realized that incorporating TMIGD2 into CAR-T cells could help them overcome the challenges presented by solid tumors. Solid tumors create a hostile microenvironment with factors such as low-oxygen levels and immune checkpoints, which can suppress immune attacks by T cells.Dr. Zang stated that solid tumors’ dense connective tissue network presents a challenge for penetrating with current treatments. He suggested that using TMIGD2 as a costimulatory protein could help activate CAR-T cells and improve their ability to reach and persist within solid tumors. These new CAR-T therapies were tested on mice with pancreatic, lung, and glioblastoma tumors, and the most effective one had both the novel antibody and the TMIGD2 protein. This specific CAR showed promising results in binding T cells to cancer cells with the aim of targeting the B7-H3 antigen.Dr. Zang has named a new CAR-T therapy TMIGD2 Optimized Potent/Persistent (TOP) CAR. This TOP CAR has shown to be the best choice for treating pancreatic, lung, and glioblastoma tumors in mice. For instance, TOP CAR treatment resulted in 7 out of 9 mice with glioblastoma tumors surviving, while the maximum survival achieved by other CAR-T therapies was 3 out of 9 mice. It also showed superior effectiveness and safety compared to other treatments. Dr. Zang plans to further develop TOP CAR into a platform that can target B7-H3 as well.Einstein holds the intellectual property rights for Dr. Zang’s research in the field of cancer treatment. They are seeking commercial partners to help advance their novel TOP CAR therapy into clinical trials for various types of solid tumors, such as brain, liver, pancreas, ovary, prostate, lung, bladder, and colon cancer. In addition to TOP CAR therapy, Dr. Zang has also developed two other anti-cancer drugs currently undergoing phase 1 and phase 2 clinical trials in the US and other countries. The research paper is titled “TOP CAR wi”.The TMIGD2 is being studied as a potential costimulatory domain in CAR cells for the treatment of solid tumors in humans. Authors from Einstein include Devin Corrigan, Xiang Yu Zheng, Phillip M. Galbo Jr., Shan Wang, Yao Liu, Yau Wei, Linna Suo, Wei Cui, and Deyou Zheng. Other authors include Nadia Mercado from Brown University School of Public Health and Cheng Cheng Zhang from the University of Texas Southwestern Medical Center. Dr. Zang and Mr. Nishimura have pending patents related to chimeric antigen receptors with a TMIGD2 costimulatory domain.; and Methods for targeting B7-H3 (CD276) with chimeric antigen receptors. Dr. Zang has a pending patent for Monoclonal antibodies against IgV domain of B7-H3 and their uses. The other authors have no conflicts of interest.
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