Researchers have developed a new chimeric antigen receptor (CAR) T-cell therapy which could one day bring the life-saving benefits of the treatment to patients with acute myeloid leukaemia (AML).
The method developed by researchers at Massachusetts General Hospital (MGH), USA, includes combining CAR-T therapy with a drug to increase the number of targets on tumour cells, and re-engineering the CAR to help the T cells adhere better to those targets.
Their findings are published in Cancer Cell.
CAR-T therapy relies on T cells being able to identify antigens that are either unique to cancer cells or are present in greater numbers on normal cells than on malignant cells.
For lymphoid malignancies, such as acute lymphoblastic leukaemia and B-cell lymphomas, targeting tumours can inadvertently lead to a reduction the number of normal antibody-producing B cells. This loss can be compensated for by replacing immunoglobulins that B cells normally make, the researchers say.
However, the side-effects of CAR-T therapy in AML is often more problematic. “In contrast, the normal counterparts to acute myeloid leukaemia are myeloid cells, which are involved in fighting infections. Unfortunately, you can’t live without these for very long,” said Dr Mark B. Leick, first author of the study, from the Cellular Immunotherapy program at the MGH Cancer Center.
Previous attempts to treat advanced AML with CAR-T therapy have failed because of the lack of a suitable antigen, because the treatment kills large numbers of healthy normal cells as well as cancer cells.
The team from MGH, led by Dr Marcela Maus, started with a CAR-T construct directed against the CD70 antigen, which is present in larger numbers on AML cells than on normal myeloid cells. Crucially, it is not present on normal haematopoietic stem cells.
This CAR-T alone was only modestly effective against AML in animal models. However, using the AML drug azacitidine increased the number of CD70 antigens on cancer cell surface, which improved the efficiency of the CAR-T therapy.
Dr Leick said the team was also able to overcome a problem in an older version of the CAR T cell to target AML.
“AML cells secrete an enzyme, a proteinase, that is essentially able to decapitate the CAR T cell, and so we localised where that cut takes place, and we modified that region, so now the CAR T cells bind tighter to the tumour and kill it more effectively,” he said.
Combining these two approaches – the new re-engineered CAR-T cell therapy with azacytidine – was significantly more effective at controlling AML cells in mice compared to previous version of the CAR-T cell therapy.
Lead researcher Dr Marcela Maus said: “We are excited for the therapeutic potential of this new CAR T cell product, and hope that we can offer it to patients with acute myeloid leukemia soon.”
Source: Leick MB, Silva H, Scarfò I, Larson R, Choi BD, Bouffard AA, Gallagher K, Schmidts A, Bailey SR, Kann MC, Jan M, Wehrli M, Grauwet K, Horick N, Frigault MJ, Maus MV (2022) “Non-cleavable hinge enhances avidity and expansion of CAR-T cells for acute myeloid leukemia.” Cancer Cell, doi: 10.1016/j.ccell.2022.04.001
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