New method could bring life-saving benefits of CAR T-cell therapy to patients with acute myeloid leukemia

Massachusetts General Hospital (MGH) researchers have developed a new treatment strategy that has the potential to bring the life-saving benefits of chimeric antigen receptor (CAR T) cell therapy to patients with acute myeloid leukemia ( AML), the most common form of leukemia in adults.

The method involves a combination of drug therapy to increase the number of targets on tumor cells, and a technical approach to help therapy adhere more tightly and sustainably to those targets.

They describe their work in a study published online in the journal Cancer cell.

CAR T therapy has revolutionized the management of patients with advanced cancers of the blood system. It involves harvesting a patient’s T cells, which are key components of the immune system, and genetically modifying them to recognize a specific target (antigen) on the surface of cancer cells. The cells are then grown in the lab and returned to the patient’s bloodstream, where they trigger an enhanced tumor-killing immune response.

CAR T therapy relies on the ability of T cells to identify antigens that are either unique to cancer cells or present in much greater numbers on normal cells than on malignant cells.

For lymphoid malignancies such as acute lymphoblastic leukemia and B-cell lymphomas, which arise from white blood cells, tumor targeting can also deplete the population of normal antibody-producing B cells, but clinicians can compensate for the loss of normal cells by replacing the immunoglobulins that B cells normally make.

In contrast, the normal counterparts of acute myeloid leukemia are myeloid cells, which are involved in fighting infection. Unfortunately, you can’t live without it for very long.”


Mark B. Leick, MD, Senior Author, Cellular Immunotherapy Program Investigator, MGH Cancer Center

Previous attempts to treat advanced AML with CAR T therapy have been thwarted by the lack of an appropriate antigen and “off-target” effects when the treatment kills large numbers of healthy normal cells as well as cancerous cells.

Leick, along with principal investigator Marcela V. Maus, MD, PhD, director of cellular immunotherapy at the MGH Cancer Center, and colleagues, started with a CAR T construct directed against an antigen called CD70 that is present in greater numbers on AML cells than on normal myeloid cells. CAR T alone was only modestly effective against AML in animal models, but its combination with the FDA-approved AML drug azacitidine increased the number of CD70 antigens on the surface of cancer cells .

“We were able to show that through the combination of the two, we achieved better tumor cell destruction,” he says.

Additionally, unlike most CARs that use mouse-derived antibodies to target the antigen, which can cause an adverse immune reaction, the CAR used in this study relies on a kind of natural molecular linkage known as ligand to bind tightly to the antigen. , thus avoiding the possibility that the immune system will recognize the tumor-killing machinery as foreign and try to reject it.

Finally, they overcame a problem that plagued an older version of the CAR T cell to target AML.

“The AML cells secrete an enzyme, a proteinase, which is basically able to decapitate the CAR T cell, and so we pinpointed where that cut takes place, and we changed that region, so now the CAR T cells bind more tightly to the tumor and kill more effectively,” says Leick.

“We are excited about the therapeutic potential of this new CAR T cell product and hope that we will soon be able to offer it to patients with acute myeloid leukemia,” says Maus.

The study was supported by grants from the National Institutes of Health, the American Society of Clinical Oncology, the Swiss National Science Foundation and the Gabrielle’s Angel Foundation.

Source:

Massachusetts General Hospital

Journal reference:

Leick, MB, et al. (2022) Non-cleavable hinge enhances CAR-T cell avidity and expansion for acute myeloid leukemia. cancer cell. doi.org/10.1016/j.ccell.2022.04.001.

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