CAR-T细胞治疗,纳米抗体 z-bo 2020-09-29 440

　　Most CAR-T cell therapies need to target cancer cell-specific antigens. Currently, there are new methods to target the environment around the tumor. The method is derived from natural "nanobodies" produced by alpacas, camels and llamas. Using this method in a mouse model, researchers have successfully controlled melanoma and colon cancer, which are solid tumors that cannot currently be treated with CAR-T cell therapy.

　　Bryson and Sanchez, two alpacas that produce "nanobodies". These "nanobodies" help promising CAR-T cell therapy kill solid tumors.

　　In 1989, two undergraduates from the Free University of Brussels (Free University of Brussels) accidentally discovered an unknown antibody while testing frozen camel serum. This is a miniature version of a human antibody, consisting of only two heavy chains instead of two light chains and two heavy chains. Their final report stated that the presence of antibodies was confirmed not only in camels, but also in llamas and alpacas. Thirty years later, in this week’s PNAS magazine, researchers from Boston Children’s Hospital and Massachusetts Institute of Technology showed that these mini-antibodies can be further reduced to form so-called nanobodies. This may help solve problems in the oncology field. Create CAR-T cell therapy to work in solid tumors. Chimera Antigen Receptor (CAR) T cell therapy uses genetic engineering to modify the patient's own T cells to better attack cancer cells. This provides a broad prospect for the development of hematological malignancies. For example, Dana-Farber/Boston Children's Cancer and Hematology Center is currently using CAR-T cell therapy to treat relapsed acute lymphoblastic leukemia (ALL).

　　However, CAR-T cells still face major challenges in removing solid tumors. It is difficult to find tumor-specific proteins that can be used as safe targets for solid tumors. At the same time, solid tumors are also protected by extracellular matrix. The extracellular matrix is a supporting network of proteins that act as a barrier. At the same time, immunosuppressive molecules can also inhibit the attack on T cells.

　　CAR-T cell rethinking

　　For 20 years, Belgium basically has antibody patents. But since the patent expired in 2013, the situation has changed.

　　Boston Children and the principal investigator of PNAS research, an immunologist of the Molecular Medicine Project, Dr. Hidde Ploegh, said: “Many people are learning this field and are beginning to notice the unique characteristics of Nanobodies.” Positioning ability. Ploegh and his team of Boston Children's Hospital are collaborating with Dr. Noo Jalikhani and Dr. Richard Hynes of the Koch Cancer Institute of MIT to carry nanobodies to provide a contrast agent that can accurately show metastatic cancer. I used

　　Hynes team turned the nanobody into the extracellular matrix (ECM) of the tumor, the environment around the cancer cell, rather than the cancer cell itself. This marker is common in many tumors, but usually does not appear in normal cells. Pulog said: "We and Hines Lab are one of the few laboratories actively researching this approach to the tumor microenvironment. Most laboratories are looking for tumor-specific antigens."

　　Target the tumor microenvironment

　　Ploegh and his team applied this idea to CAR-T cell therapy, aiming to solve the factors that are difficult to treat solid tumors. The CAR-T cells they created are full of Nanobodies, which can carry signals that recognize specific proteins in the tumor environment and direct them to kill the cells that bind to them. One of these proteins, EIIIB, is a variant of fibronectin, found only in the new blood vessels that nourish tumors. The other is PD-L1, an immunosuppressive protein used by most cancers to suppress nearby T cells.

　　Jessica Ingram, a biochemist at the Dana-Farber Cancer Institute, Ploegh’s partner and co-author of the paper, will drive to Amherst, Massachusetts, from two alpacas Bryson Collect T with Sanchez. The cells are injected with the desired antigen, blood is collected, and further processed in Boston to produce mini-antibodies. The treatment of melanoma and colon cancer tested two independent mouse models of melanoma and a mouse model of colon adenocarcinoma. Nanobody-based CAR-T cells can kill tumor cells and significantly slow down tumor growth, and can improve the survival of animals without significant side effects.

　　Ploegh believes that manipulated T cells can work together through a variety of factors. They cause damage to tumor tissue and usually stimulate an inflammatory immune response. Targeting EIIIB can damage blood vessels by reducing the tumor’s blood supply while increasing its permeability to cancer drugs.

　　Plog said: “Interfering with local blood supply and causing vascular leakage may improve the delivery of other people who are difficult to access. I think this should be part of comprehensive treatment.” Future directions

　　Ploegh believes that his team’s approach may help many solid tumors. He is particularly interested in testing nanobody-based CAR-T cells in pancreatic cancer and cholangiocarcinoma models. Cholangiocarcinoma is a cholangiocarcinoma that Ingram died in 2018. Plog said that the technology itself can be further developed.

　　Plog said: Nanobodies may carry cytokines that enhance the immune response to tumors, toxic molecules that kill tumors, and radioisotopes that irradiate tumors at close range. CAR-T cells are a pioneer in breaking through the gates. This element will complete the "task" later. In theory, T cells can be equipped with multiple chimeric antigen receptors to achieve higher accuracy. This is the goal we want to pursue.

　　YushuJoyXie is the Boston Children’s Cellular and Molecular Medicine Project, and a graduate student from the Koch Institute at MIT is also the first author of the paper. Supporters include the Lustgarten Foundation, the National Science Foundation, the National Institutes of Health, the American Society of Gastroenterology, the Howard Hughes Medical Institute Department of Defense and the National Cancer Institute.