Abstract
Despite significant progress over the last few decades in the treatment of acute myeloid leukemia (AML), there still remains a major unmet medical need for this disease. Immunotherapy approaches for redirecting pan CD3+ T cells to target leukemia blasts have shown limited efficacy in clinical trials and often accompanied with severe toxicity in AML patients. We designed an alternative engager molecule (Anti-TRGV9/anti-CD123), a bispecific antibody that can simultaneously bind to the Vγ9 chain of the Vγ9Vδ2+ γδ T cell receptor and to AML target antigen, CD123, to selectively recruit Vγ9+ γδ T cells rather than pan T cells to target AML blasts. Our results suggest that prototypic bispecific antibodies (a) selectively activate Vγ9+ γδ T cells as judged by CD69 and CD25 surface expression, and intracellular Granzyme B expression, (b) selectively recruit Vγ9+ γδ T cells into cell–cell conjugate formation of γδ T cells with tumor cells indicating selective and effective engagement of effector and target tumor cells, and (c) mediate γδ T cell cytotoxicity (in vitro and in vivo) against tumor antigen-expressing cells. Collectively, these findings suggest that selectively redirecting Vγ9+ γδ T cells to target AML blasts has a potential for immunotherapy for AML patients and favors further exploration of this concept.
Highlights
Acute myeloid leukemia (AML) is a fast-growing disease that occurs in large, immature white blood cells leading to leukemia [1]
Our results presented in this report suggest that selectively redirecting Vγ9+ γδ T cells to target AML blasts has a potential for immunotherapy for AML patients
We focused our studies on circulating γδ T cells that express heterodimers of Vγ9/Vδ2 TCR chains because they manifest potent anti-cancer functions [20]
Summary
Acute myeloid leukemia (AML) is a fast-growing disease that occurs in large, immature white blood cells leading to leukemia [1]. Chemotherapy and hematopoietic stem cell transplantation are some treatments options; ineligible patients survive only for less than a year [2, 3]. As the role of T cells in the anti-cancer immune response is strongly supported and correlates with a favorable clinical prognosis in many cancers [4], novel strategies to redirect T cells for immunotherapy have been increasingly investigated for multiple cancers including AML [5,6,7,8].
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