CAR T drives acute myeloid leukemia into submission in pre-clinical
studies

Date:
April 28, 2022
Source:
Massachusetts General Hospital
Summary:
Investigators have devised a novel method for improving CAR T
therapy through a drug combination and cellular engineering that
improves the strength and durability of the tumor-killing effect
of a CAR T directed against acute myeloid leukemia.



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


==========================================================================
The method involves a combination of drug therapy to expand the number of targets on tumor cells, and an engineering approach to help the therapy
adhere more tightly and durably to those targets.

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

CAR T therapy has revolutionized the care 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 engineering
them to recognize a specific target (antigen) on the surface of cancer
cells. The cells are then expanded in the laboratory and returned to
the patient's bloodstream, where they mount 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 are 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, targeting tumors
can also deplete the population of normal antibody-producing B cells,
but clinicians can compensate for the loss of normal cells by replacing immunoglobulins that B cells normally make.



==========================================================================
"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," says lead author Mark
B. Leick, MD, investigator the Cellular Immunotherapy program at the
MGH Cancer Center, Previous attempts to treat advanced AML with CAR
T therapy have been stymied by the lack of a suitable antigen, and by "off-target" effects when the treatment kills large numbers of healthy
normal cells as well as cancer cells.

Leick, with senior researcher 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 larger numbers on AML cells than on normal myeloid cells. The
CAR T alone was only modestly effective against AML in animal models,
but combining it with the FDA- approved AML drug azacitidine increased
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," he says.

In addition, unlike most CARs that use antibodies derived from mice
to target the antigen, which 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.

Lastly, they overcame a problem that bedeviled 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 localized where that cut takes
place, and we modified that region, so now the CAR T cells bind tighter
to the tumor and kill it more effectively," Leick says.

"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," saysMaus.

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


========================================================================== Story Source: Materials provided by Massachusetts_General_Hospital. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Mark B. Leick, Harrison Silva, Irene Scarfo`, Rebecca Larson,
Bryan D.

Choi, Amanda A. Bouffard, Kathleen Gallagher, Andrea Schmidts,
Stefanie R. Bailey, Michael C. Kann, Max Jan, Marc Wehrli,
Korneel Grauwet, Nora Horick, Matthew J. Frigault, Marcela
V. Maus. Non-cleavable hinge enhances avidity and expansion of
CAR-T cells for acute myeloid leukemia.

Cancer Cell, 2022; DOI: 10.1016/j.ccell.2022.04.001 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220428125358.htm

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