CAR-T cells used to target glioblastoma

Immunotherapy is the new weapon against cancer. Building on existing research, a team of researchers at Mbadachusetts General Hospital has developed a way to increase the effectiveness of immunotherapy in a common and lethal form of cancer. brain called glioblastoma. Their study titled "CAR-T cells secreting BiTE avoids escape of antigen without detectable toxicity", was published in the last issue of the journal Nature Biotechnology.

Brain MRI showing left frontal gliblastoma. Image Credit: O_Akira / Shutterstock

The team of researchers has explained that one of the methods of cancer immunotherapy is called "T-receptor (TTR) therapy of chimeric antigens". CAR-T therapy usually collects the patient's immune cells or T cells, and these cells are genetically modified in the laboratory to recognize specific antigen targets present on cancer cells. These genetically engineered T cells are now equipped to recognize and kill cancer cells and save normal, healthy cells from the body. They are then reinjected into the patient's body. Currently, the US Food and Drug Administration (FDA) has approved two CAR-T cell products for the treatment of Non-Hodgkin's Lymphoma (NHL) and Acute Lymphoblastic Leukemia (ALL) . These tumors are lymphatic system and blood respectively.

The team explained that solid tumors are difficult to treat with this method of immunotherapy and have therefore never been tried. Other solid tumors such as glioblastomas are also difficult to treat with conventional chemotherapy because large drug molecules rarely cross the blood-brain barrier. Lead author Marcela V. Maus, MD, PhD, Director of Cellular Immunotherapy at the MGH Cancer Center and Assistant Professor of Medicine at Harvard Medical School (HMS), explained that glioblastoma immunotherapy is also a challenge .

Maus said: "We had already made CAR T cells for glioblastoma and one of the challenges of glioblastoma is that not all tumor cells express the target that a T cell can reach. The team is interested in epidermal growth factor III receptor (EGFRvIII) variant, a mutated protein that causes cancer and is present in many, but not all, glioblastomas. The team used CAR-T cells to target another "wild type" EGFR found in all glioblastomas. The team explains that targeting this EGFR was another challenge because it is also found in other healthy cells of the body. This problem has been solved by transferring genetically modified CAR-T cells into the cerebrospinal fluid at the base of the brain. Once CAR-T cells have reached the brain, they have been designed to secrete a "bi-specific T lymphocyte developer" or "BiTE", which are actually antibodies that direct these T lymphocytes to a specific target, like "smart bombs," the researchers write. .

The team therefore used CAR-T cells with their special BiTE antibodies to target glioblastomas. The problem they had faced was that the BiTEs were too big to cross the blood-brain barrier if they were administered intravenously. This was overcome when CAR-T cells carrying BiTE antibodies were directly injected into the cerebrospinal fluid. According to Maus, CAR cells secreting BiTE "may have a local tumor effect by targeting the second antigen, thereby overcoming this tumor heterogeneity and targeting two things at once. But since it is produced on the other side of the blood-brain barrier and in small amounts, it does not cause toxicity to other organs. "

The team tested their modified BTE-secreting CAR-T cells on animal models of human glioblastomas and noted that this combination could effectively eliminate 80% of the tumors. The team concluded in its study that "BiTE-EGFR was locally effective but was not systemically detected after intracranial delivery of CART-BiTE cells. In contrast to EGFR-specific CAR-T cells, CART-BiTE cells did not result in in vivo toxicity against human skin grafts. "

Lead author Bryan D. Choi, MD, of the Department of Neurosurgery at the Montreal General Hospital, added that he hoped that this technique could also work with other solid tumors.

The study was funded by grants from the Damon Runyon-Rachleff Innovation Award and Stand Up to Cancer, from the National Institutes of Health and others.

About CAR-T cells

Renier J. Brentjens, MD, Ph.D., of the Memorial Sloan Kettering Cancer Center in New York, a pioneer of the T-cell field of CAR, said the use of this therapy equates to "giving a drug alive to patients. "

T cells here are the "beasts of burden of the immune system". They are separated from the patient's blood and then, using genetically modified viral vectors, these T cells are genetically engineered to produce receptors on their surface. These receptors are called "chimeric antigen receptors or CARs". Carl June, MD, Abramson Cancer Center of the University of Pennsylvania, one of the leading researchers on CAR-T cell therapy, said that these receptors are "synthetic molecules, they do not exist not naturally. These receptors allow the cells to identify the antigens on the cancer cells.

These CART cells are then multiplied and reinjected into the patient's body after treatment with chemotherapy. As expected, these T cells multiply in the patient's body and target and destroy the cancer cells carrying the antigen on their surface.