Revolutionary CAR-T cell therapy aims to move beyond blood cancer | Health and wellness

There is a cancer treatment that has revolutionized the prediction of blood tumors in just ten years. This is CAR-T cell therapy, a huge work of genetic engineering that involves extracting T cells (a type of immune cell responsible for the body’s defense) from a patient’s body, modifying them in the laboratory to make them more effective, and returning them to their original state. them to the patient so that he can better fight the tumor. It looks like science fiction, its promoters admit, but it is so real that it has already achieved thousands of unimaginable victories. And those that remained. CAR-T therapy has been successful in treating some hematologic cancers, such as some leukemias or lymphomas, but it still has one unresolved issue: solid tumors, where it has not produced favorable results. The investigation was published this Wednesday in the magazine Science achievementsHowever, this opens up new possibilities for expanding this revolutionary cell therapy beyond blood cancer: In a study in animal models, scientists from the Montefiore Einstein Cancer Center in New York showed that a more potent and optimized version of CAR-T improves the survival of tumor-bearing mice brain, pancreas and lungs.

The biology of solid tumors, much more complex, has become an important factor for the successful implementation of CAR-T therapies beyond blood cancers. Dr. very strong immunosuppressive tumor microenvironment that inhibits CAR-T persistence and causes CAR-T exhaustion (lack of function) in natural conditions“, Explain. It is also difficult to detect tumor antigens on the surface of malignant cells, which are molecules that act as a kind of bait, an “introduction letter” to the tumor that helps the immune system determine which cells are malignant. In CAR-T therapy, the choice of antigen is key because the activity of genetically modified T lymphocytes is directed against tumor cells that express that particular antigen.

In his new study, Zang, who is also the founding director of the Institute for Cancer Immunology at Montefiore Einstein Comprehensive Cancer Center, joins the scientific community’s efforts to create new CAR-Ts that work better in solid tumors. And this was done by redesigning parts of the structure of these molecular machines to create a more efficient and powerful CAR-T. Their therapy, which uses two new mechanisms, was tested in mice implanted with several types of human solid tumors.

The CAR-T developed by Zang’s team—called TOP CAR (TMIGD2 Optimized Potent/Persistent CAR)—targets a new bait, the B7-H3 antigen, a molecule found in tumor cells that is uncommon in healthy tissue. “Our previous studies showed that B7-H3 is widely expressed not only in human solid tumor cells, but also in the tumor vasculature, whereas in normal tissues it has very limited expression,” explains the scientist. This new target, Zang says, has advantages over others because “it can target many types of solid tumors” that present this antigen; “has an anti-angiogenic 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 not only improved the target of the attack, he enhanced his CAR-T with a new costimulator that helps activate T cells 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, to prevent B7-H3 from interfering with the ability of T cells to attack and destroy cancer cells and their blood vessels,” justifies scientist in a press release from his institution.

In an email exchange, Zang goes deeper into this CAR-T redesign and highlights the benefits of this new costimulator, which is completely different from that used in other FDA-approved CAR-T therapies, he says. He. “Since 2017, the FDA has approved six CAR-T therapies that use CD28 or 4-1BB as costimulators, which play an important role 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 found a lower percentage of exhausted cells, so the CAR-T cells function better; higher percentage of central memory cells, so CAR-T cells have better function and durability; a higher proportion of CD8/CD4 T cells in tumors, so CAR-T cells have better ability to destroy tumors and fewer side effects; and they produce fewer cytokines, so CAR-T cells have better persistence and fewer cytokine-related side effects,” he notes.

Regarding survival in the animal models studied, Zang notes that “compared with the third generation of CAR-T, TOP CAR showed therapeutic efficacy.” And he gives a couple of examples: TOP CAR allowed seven out of nine mice with glioblastoma (a brain tumor) to survive, while with another CAR-T only three out of nine survived; In human pancreatic tumor models, four of seven mice treated with TOP CAR survived, while only one of seven managed to survive after receiving third-generation CAR-T. “Based on our results, we want to conduct clinical trials of this new therapy in cancer patients in the near future, especially in solid tumors resistant to immune checkpoint inhibitors, such as brain, liver, pancreatic, ovarian, prostate, etc. etc.,” the scientist promotes.

First step

“Zang’s study is just the first step, a new path opened in the path that various research groups around the world are blazing to improve CAR-T and adapt it to different tumors,” explains Alberto Mussetti, director of the department of hematopoietic cell transplantation. Cell therapy from the Catalan Institute of Oncology L’Hospitale: “In solid tumors, CAR-T works very little or not at all. In many cases, because they are unable to attack solid tumors. This study may be a promising strategy to overcome these resistances and is added to the list of efforts to create new CAR-Ts,” explains a hematologist who was not involved in this study.

For his part, Francisco Aya, oncologist at the Hospital Clinic of Barcelona, ​​recalls that the great difficulty in delivering CAR-T to solid tumors lies in “finding a target antigen that is specific to the tumor and not shared with other healthy tissues.” , and also that this therapy reaches the cancer mass well because these solid tumors can have a microenvironment around them that suppresses immune system attack. “And in addition to recognizing the malignant cell, these CAR-Ts must be accompanied by a costimulator that facilitates the cytotoxic response (of immune system cells to kill the tumor).” The doctor, who was also not involved in Zang’s research, said the study “found another costimulator that appears to be safer and improves the type of response” of the immune system. But he cautions that the results so far are in vivo and in vitro, and it remains to be seen whether the results will translate to human testing. “This study is a reflection of the efforts being made to develop these treatments, but it is too early to be optimistic about these strategies. “I wouldn’t throw bells in the air,” he notes.

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