Promising novel target identified for AML

Vasoactive intestinal peptide (VIP) is an immunosuppressive peptide which is overexpressed in acute myeloid leukaemia (AML), and VIP receptor antagonist peptides have been associated with the induction of protective immunologic memory in mice with leukaemia and activated human T cells in vitro. According to the research team investigating this novel target in AML, the development of a longer-acting form of VIP receptor antagonist is underway.

“VIP is a neuropeptide that is known to be secreted by myeloid progenitor cells, nerves, and activated T cells, binding on receptors on dendritic cells and naïve T cells, leading to tolerogenic dendritic cells, and ultimately to regulatory T cells, which downregulate Th1 and upregulate Th2 polarisation,” explained Prof. Edmund Waller (Emory University, GA, USA) [1]. “These regulatory T cells have been shown to inhibit activated T cells,” added Prof. Waller. A research team looked at the possibility to target VIP in AML. “We know that VIP binds to surface receptors VPAC1 and VPAC2, which are present on the T cells of humans and mice,” Prof. Waller continued.

The authors used in silico screening to map a library of alternative peptide sequences to identify peptide sequences with high binding affinity to human VPAC1 and VPAC2. Subsequently, the investigators selected the peptide sequences with potent antileukaemic activity in mice.

Various VIP receptor antagonists were associated with improved survival and delivered durable remissions in mice with leukaemia. Furthermore, higher dose intensities of VIP receptor antagonist therapies were linked to superior survival outcomes compared with lower dose intensities. “Mice that survived the initial leukaemic challenge after treatment with the VIP receptor antagonist were resistant to subsequent re-challenges with the same leukaemia,” added Prof. Waller. Finally, VIP receptor antagonist peptides activated human T cells in vitro.

“VIP receptor antagonists enhance T-cell dependent anti-leukaemic effects,” said Prof. Waller. “A longer-acting form of VIP receptor antagonists is currently being developed.”

1. Waller EK, et al. Novel immunotherapy for AML. OS21-03, European Society for Blood and Marrow Transplantation (EBMT) 49^th Annual Meeting, 23–26 April 2023, Paris, France.

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Posted on 14 June, 2023