Promising novel target for AML identified

In acute myeloid leukaemia (AML), which overexpresses the immunosuppressive peptide VIP, VIP receptor antagonist peptides were associated with the induction of protective immunologic memory in mice with leukaemia and activated human T cells in vitro. According to the research team that investigated this novel target in AML, the development of a longer-acting form of VIP receptor antagonists 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 polarisation and upregulate Th2 polarisation,” explained Dr Edmund Waller (Emory University, GA, USA). “These regulatory T cells have been shown to inhibit activated T cells,” added Dr Waller. A research team looked at the opportunity 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,” Dr Waller continued. The authors used in silico screening to screen 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 anti-leukaemic 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 Dr Waller. Finally, VIP-receptor antagonist peptides activated human T cells in vitro.

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

1. 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 2 May, 2023