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Pre-clinical Trial Reveals That Antigen Receptor Therapy Pushes Leukemia Into Submission

Researchers at the Massachusetts General Hospital or MGH have developed a treatment method, which can bring the life-saving benefits of chimeric antigen receptor T-cell therapy or CAR T to patients suffering from acute myeloid leukemia or AML. This is the most common form of leukemia affecting the adult population. The findings of the research were published in the journal Cancer Cell.

The treatment method involves using a combination of drug therapy and an engineering approach. While the drug therapy will expand the number of targets on tumor cells, the engineering approach will help use the therapy more strictly to those targets.

Under the CAR T therapy, a patient's T cells are harvested. The T-cells are the key components of the immune system and they are genetically modified to recognize a specific target or antigen on the surface of cancer cells. The cells are then enlarged in the laboratory and returned to the patient's bloodstream, where they begin an advanced tumor-killing immune response.

CAR T therapy works by using the ability of T cells to identify antigens, which are either unique to cancer cells or are present in greater numbers on normal cells, when compared to malignant cells.

For lymphoid tumors like acute lymphoblastic leukemia and B-cell lymphomas, which arise from white blood cells, targeting tumors can also decrease the population of normal antibody-producing B cells, but doctors compensate for the loss of normal cells by replacing immunoglobulins, which B cells normally make.

Commenting on the developments, lead author of the study, Mark B Leick, MD, investigator the Cellular Immunotherapy program at the MGH Cancer Center, said, "In contrast, the normal counterparts to acute myeloid leukemia are myeloid cells, which are involved in fighting infections. Unfortunately, you can't live without these for very long."

Leick, along with his colleagues, started with a CAR T construct directed against an antigen called CD70, which is present in larger numbers on AML cells than on normal myeloid cells. When used alone, the CAR T was only modestly effective against AML in animal models, but in combination with the FDA-approved AML drug azacitidine led to an increase in the number of CD70 antigens on cancer cell surfaces.

"We were able to show that through the combination of the two, we got better killing of the tumor cells," Leick said.

In addition, unlike most CARs, which use antibodies derived from mice to target the antigen, that can cause an unwanted immune reaction, the CAR used in this study relies on a kind of a natural molecular bond known as a ligand to bind tightly to the antigen, thereby avoiding the possibility that the immune system would recognize the tumor-killing machinery as foreign and try to reject it.

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