There is a cancer treatment that, in just a decade, has revolutionized the prognosis of blood tumors. It is CAR-T cell therapy, an immense work of genetic engineering that consists of extracting T lymphocytes from the patient – a type of immune cells that are responsible for the body’s defense -, modifying them in the laboratory to make them more effective and returning them to the patient. so they can better fight the tumor. It seems like science fiction, its promoters admit, but it is as real as it has already given away thousands of unthinkable victories. And the ones that remain. CAR-T therapy has been successfully established in the treatment of a handful of hematological cancers, such as some leukemias or lymphomas, but it still has one pending issue: solid tumors, where it has not achieved favorable results. An investigation published this Wednesday in the magazine Science AdvancesHowever, it opens a new vein to take this revolutionary cell therapy beyond blood cancer: in a study in animal models, scientists at the Montefiore Einstein Cancer Center in New York have shown that a more powerful and optimized version of CARs -T improves survival in mice with brain tumor, pancreatic and lung cancer.
The biology of solid tumors, much more complex, has been the big stone in the shoe to successfully land CAR-T therapy beyond blood cancer. Dr. very strong immunosuppressive tumor microenvironment, which inhibits CAR-T persistence and induces CAR-T exhaustion (lack of function) in vivo“, Explain. It is also not easy to find tumor antigens on the surface of malignant cells, which are molecules that function as a kind of decoy, a letter of introduction to the tumor that helps the immune system identify which cells are malignant. In CAR-T therapies, antigen selection is key because the activity of genetically modified T lymphocytes is directed against tumor cells that express that particular antigen.
In his new research, Zang, who is also founding director of the Cancer Immunology Institute at Montefiore Einstein Comprehensive Cancer Center, has joined the scientific community’s attempts to build new CAR-Ts that work better in solid tumors. And he has done it by redesigning parts of the structure of these molecular machines to create a more efficient and powerful CAR-T. His therapy, which uses two novel mechanisms, was tested in mice implanted with several types of human solid tumors.
The CAR-T designed by Zang’s team—it is called TOP CAR (TMIGD2 Optimized Potent/Persistent CAR)—targets a new decoy, the B7-H3 antigen, a molecule present on tumor cells and unusual in tissue. healthy. “Our previous studies demonstrated that B7-H3 is widely expressed not only in human solid tumor cells, but also in the tumor vasculature, while it has a very limited expression in normal tissues,” explains the scientist. This new target, Zang assures, has advantages over others because “it can target many types of solid tumors” that present this antigen; “it has an antiangiogenic effect,” because it prevents the formation of blood vessels through which cancer can feed; and reduces the immunosuppression generated by this antigen in the tumor microenvironment.
But Zang has not only perfected the target of attack, he has strengthened his CAR-T with a new costimulator that helps activate T lymphocytes to attack tumor cells. “We wanted our CARs to not only bind T cells to solid tumors, but also, by specifically binding to B7-H3, prevent B7-H3 from interfering with the T cells’ ability to attack and destroy cancer cells and their blood vessels,” the scientist justifies in a press release from his institution.
In an email conversation, Zang delves into this redesign of the CAR-T and underlines the advantages of this new costimulator, completely different from that used in other CAR-T therapies approved by the FDA (the US drug agency), he says. “Since 2017, the FDA has approved six CAR-T therapies that use [las proteínas] CD28 or 4-1BB as costimulators, which play important roles in CAR-T cell activation/exhaustion and persistence. Our TOP CAR uses TMIGD2 as a costimulator, which is completely different from FDA approved CAR-T cells. Our TOP CAR established a lower percentage of exhausted cells, so CAR-T cells have better function; a higher percentage of central memory cells, so CAR-T cells have better function and persistence; a higher proportion of CD8/CD4 T cells within tumors, so CAR-T cells have a better ability to destroy tumors and fewer side effects; and they produced fewer cytokines, so CAR-T cells have better persistence and fewer side effects associated with cytokines,” he celebrates.
In terms of survival, in the animal models studied, Zang points out that, “compared to the third generation of CAR-T, the TOP CAR showed therapeutic efficiencies.” And he gives a couple of examples: the TOP CAR allowed seven of nine mice with glioblastoma (a brain tumor) to survive, while with the other CAR-T only three of nine did; In human pancreatic tumor models, four of seven mice treated with TOP CAR survived, while only one of seven managed to live after receiving third-generation CAR-T. “Based on our results, we want to bring this new therapy into clinical trials in cancer patients in the near future, particularly in solid tumors resistant to immune checkpoint inhibitors, such as cancers of the brain, liver, pancreas, ovary, prostate, etc.”, advances the scientist.
A first step
Zang’s study is just a first step, a new path opened in the path that various research groups in the world are paving to perfect CAR-T and adapt them to different tumors, explains Alberto Mussetti, director of the Transplant Unit. of Hematopoietic Cells and Cellular Therapy of the Catalan Institute of Oncology of L’Hospitalet: “For solid tumors, CAR-T works very little or not at all. In many cases, because they are not able to attack the solid tumor. This study could be a promising strategy to overcome these resistances and is added to the list of attempts to build new CAR-Ts,” explains the hematologist, who has not participated in this research.
For his part, Francisco Aya, oncologist at the Hospital Clínic of Barcelona, recalls that the great difficulties in delivering CAR-T to solid tumors are “finding a target antigen that is specific to the tumor and is not shared with other healthy tissues, and also that this therapy reaches the cancerous mass well, because these solid tumors may have a microenvironment around them that represses the attack of the immune system. “And in addition to recognizing the malignant cell, these CAR-Ts have to be accompanied by a costimulator that facilitates the cytotoxic response.” [de las células del sistema inmune para aniquilar el tumor]”. The doctor, who has not participated in Zang’s research either, assures that this study “has found a different costimulator, which seems safer and improves the type of response” of the immune system. But he warns that the findings, for now, are in vivo and in vitro and it remains to be seen if the results translate when tested in humans. “This study is a reflection of the effort being made in the development of these therapies, but it is too early to be optimistic about these strategies. “I wouldn’t throw the bells into the air,” he points out.
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