Revolutionary CAR-T cell therapy looks to break through beyond blood cancer

In just a decade, a new treatment has revolutionized the prognosis for people diagnosed with blood cancer. It’s called CAR-T cell therapy, a stunning achievement of genetic engineering that consists of extracting a patient’s T-lymphocytes — a type of immune cells that oversee an organism’s defenses — modifying them in a laboratory to make them more effective, and returning them to the patient so that they can better combat tumors. It sounds like science fiction, its creators admit, but it’s real and has already scored thousands of victories that would have been previously unthinkable. Many more lie ahead. CAR-T therapy’s success in treating several hematological cancers has been confirmed, including some leukemias and lymphomas, but there’s another condition it hopes to conquer: that of solid tumors, where it has yet to yield favorable results. Nonetheless, a study published on Wednesday in the Science Advances journal opens a new avenue that could lead this revolutionary cell therapy beyond blood cancers: in an experiment conducted on animal subjects, scientists from the New York’s Montefiore Einstein Comprehensive Cancer Center demonstrated that a more powerful and optimized version of CAR-T improves survival rates among rats with brain tumors, pancreatic, and lung cancers.

The biology of solid tumors, which are far more complex, has been a rock in the shoe of scientists when it comes to establishing CAR-T therapy’s efficacy beyond blood cancers. Doctor Xingxing Zang, oncology and hematology professor at the Albert Einstein College of Medicine and author of the study, pins this difficulty on the environment surrounding the tumor, which can hinder a treatment’s efficiency: “Solid tumors generally have a very strong immunosuppressive tumor microenvironment that inhibits the efficiency of CAR-T and induces CAR-T depletion (the absence of function) in vivo,” he explains. It’s also not easy to locate tumor antigens on the surface of malignant cells, molecules that function as a kind of decoy and the calling card of tumors, which can help the immune system to identify malignant cells. In CAR-T therapies, antigen selection is key, because the activity of genetically modified T-lymphocytes is directed towards combating tumor cells that express these particular antigens.

In his new study, Zang, who is also a professor in the microbiology and immunology department of the Montefiore Einstein Comprehensive Cancer Center, has joined the efforts of the scientific community in building new CAR-T that work more efficiently on solid tumors. He has also redesigned parts of the structure of this molecular machinery to create a more efficient and powerful CAR-T. His treatment, which uses two novel mechanisms, has been tested on mice in which various kinds of human solid tumors had been implanted.

The CAR-T designed by Zang’s team — TOP CAR (TMIGD2 Optimized Potent/Persistent CAR) — targets a new decoy, the B7-H3 antigen, a molecule present on tumor cells that is unusual in healthy tissue. “Our previous studies demonstrated the B7-H3 is amply expressed not just in human solid tumor cells, but also in tumor vasculature, while it has very limited expression in normal tissue,” says the scientist. This new target, says Zang, has advantages over others because “it can target many types of solid tumors” that present this antigen; “it has an anti-angiogenic effect,” because it prevents the formation of blood vessels through which the cancer can feed; and it reduces the immunosuppression that the antigen generates in the tumor’s microenvironment.

Zang has not just perfected the target of attack, but also strengthened his CAR-T with a new co-stimulator that helps to activate the T-lymphocytes to attack tumor cells. “We wanted our CAR not just to lead T-cells to solid tumors, but also to lead specifically to B7-H3, preventing the B7-H3 from interfering with the ability of the T-cells to attack and destroy cancerous cells and their blood vessels,” says the scientist, in a press statement published by his institution.

In an email conversation, Zang elaborates on this redesign of the CAR-T and points out the advantages of his new co-stimulator, which is completely different to those employed by other CAR-T therapies that have been approved by the FDA, he says. “Since 2017, the FDA has approved six CAR-T therapies that utilize CD28 and 4-1BB [proteins] as co-stimulators, and which perform important functions when it comes to activation/depletion and in CAR-T cell persistence. Our TOP CAR utilizes TMIGD2 as co-stimulator, which is completely different to the FDA-approved CAR-T cells. Our TOP CAR evidenced a lower percentage of depleted cells, indicating that the CAR-T cells are functioning better; a higher percentage of central memory cells, indicating that the CAR-T cells are functioning better; a greater proportion of T CD8/CD4 cells within tumors, indicating that the CAR-T cells have better ability to destroy tumors and fewer side effects; and they produced fewer cytokines, indicating that the CAR-T cells are more persistent and have fewer side effects associated with cytokines,” he says.

In terms of survival among the animal subjects that were studied, Zang says that, “in comparison with the third generation CAR-T, TOP CAR displayed therapeutic efficiency.” He offers a pair of examples: TOP CAR allowed seven of nine mice with glioblastoma (a brain tumor) to survive, whereas with other CAR-T, only three of nine survived; among the subjects with human pancreas tumors, four of the seven mice treated with TOP CAR survived, while only one of seven lived after receiving third-generation CAR-T. “Based on our results, we want to bring this new treatment to clinical trials on cancer patients in the near future, particularly on solid tumors that have been resistant to immune checkpoint inhibitors, like cancers of the brain, liver, pancreas, ovaries, prostate, etc.,” says the scientist.

A first step

Zang’s study is just a first step, a new avenue in the work that various research groups around the world are doing on perfecting CAR-T cells and adapting them to different tumors, explains Alberto Mussetti, director of the hematopoietic cell transplantation and cell therapy unit of the Catalan Institute of Oncology operated by the Catalan government’s Ministry of Health. “For solid tumors, CAR-Ts are only slightly, or not at all, effective. In many cases, that’s because they are not capable of attacking solid tumors. This study could be a promising strategy towards overcoming these resistant cases and will be added to the list of attempts to build new CAR-T,” says the hematologist, who did not participate in the study.

For his part, Francisco Aya, oncologist at the Hospital Clínic de Barcelona, brings up the fact that the major difficulties in linking CAR-Ts to solid tumors lie in “finding a target antigen specific to the tumor that is not shared with healthy tissue, and also that the therapy works safely” on the cancerous mass, because solid tumors can have a surrounding microenvironment that combats the immune system’s attacks. “And in addition to recognizing the malignant cell, CAR-Ts must be accompanied by a co-stimulator that facilitates the cytotoxic response [of the immune system’s cells in order to annihilate the tumor].” The doctor, who also did not participate in Zang’s study, says that the experiment “has found a different co-stimulator, one that seems to be safer and improves the type of response” of the immune system. But he warns that for the moment, the findings have taken place in vivo and in vitro, and it remains to be seen if its results will translate to tests on humans. “This study is a reflection of the effort that has been made in the development of these treatments, but it’s too soon to be optimistic about their strategies. I wouldn’t start celebrating just yet,” he says.

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