Selective recruitment of γδ T cells by a bispecific antibody for the treatment of acute myeloid leukemia.
Rajkumar GanesanVijaykumar ChennupatiBalaji RamachandranMichael Riis HansenSanjaya SinghIqbal S GrewalPublished in: Leukemia (2021)
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.
Keyphrases
- acute myeloid leukemia
- allogeneic hematopoietic stem cell transplantation
- end stage renal disease
- ejection fraction
- clinical trial
- newly diagnosed
- single cell
- poor prognosis
- prognostic factors
- induced apoptosis
- peritoneal dialysis
- binding protein
- signaling pathway
- drug delivery
- patient reported outcomes
- long non coding rna
- mesenchymal stem cells
- dendritic cells
- reactive oxygen species
- smoking cessation
- patient reported
- phase iii
- phase ii
- replacement therapy