Mechanism of action of DSP-7888 (adegramotide/nelatimotide) Emulsion, a peptide-based therapeutic cancer vaccine with the potential to turn up the heat on non-immunoreactive tumors.

Abstract

BACKGROUND:

Wilms' tumor 1 (WT1) is highly expressed in various solid tumors and hematologic malignancies. DSP-7888 (adegramotide/nelatimotide) Emulsion is an investigational therapeutic cancer vaccine comprising three synthetic epitopes derived from WT1. We evaluated the mechanism of action of DSP-7888 Emulsion, which is hypothesized to induce WT1-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs).

METHODS:

The ability of nelatimotide and adegramotide to induce WT1-specific CD8+ T cells and CD4+ T cells was assessed in human peripheral blood mononuclear cells (PBMCs). The ability of DSP-7888 Emulsion to induce WT1-specific CTLs in vivo was assessed using human leukocyte antigen-I (HLA-I) transgenic mice. To assess how adegramotide, the helper peptide in DSP-7888 Emulsion, enhances WT1-specific CTLs, HLA-I transgenic mice were administered DSP-7888 or nelatimotide-only Emulsion. Interferon-gamma secretion under antigen stimulation by splenocytes co-cultured with or without tumor cells was then quantified. The effects of combination treatment with DSP-7888 Emulsion and an anti-programmed cell death protein 1 (PD-1) antibody on tumor volume and the frequency of tumor-infiltrating WT1-specific T cells were assessed in HLA-I transgenic mice implanted with WT1 antigen-positive tumors.

RESULTS:

The peptides in DSP-7888 Emulsion were shown to induce WT1-specific CTLs and HTLs in both human PBMCs and HLA-I transgenic mice. Unlike splenocytes from nelatimotide-only Emulsion-treated mice, splenocytes from DSP-7888 Emulsion-treated mice exhibited high levels of interferon-gamma secretion, including when co-cultured with tumor cells; interferon-gamma secretion was further enhanced by concomitant treatment with anti-PD-1. HLA-I transgenic mice administered DSP-7888 Emulsion plus anti-PD-1 experienced significantly greater reductions in tumor size than mice treated with either agent alone. This reduction in tumor volume was accompanied by increased numbers of tumor-infiltrating WT1-specific CTLs.

CONCLUSIONS:

DSP-7888 Emulsion can promote both cytotoxic and helper T-cell-mediated immune responses against WT1-positive tumors. Adegramotide enhances CTL numbers, and the CTLs induced by treatment with both nelatimotide and adegramotide are capable of functioning within the immunosuppressive tumor microenvironment. The ability of anti-PD-1 to enhance the antitumor activity of DSP-7888 Emulsion in mice implanted with WT1-positive tumors suggests the potential for synergy.

• Authors: Natsuko Suginobe, Megumi Nakamura, Yosuke Takanashi, Hitoshi Ban, Masashi Gotoh
• Journal: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico (Clin Transl Oncol) Vol. 25 Issue 2 Pg. 396-407 (Feb 2023) ISSN: 1699-3055 [Electronic] Italy
• PMID: 36138335 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Cancer Vaccines
• Interferon-gamma
• Emulsions
• WT1 Proteins
• Peptides

Topics

• Humans
• Mice
• Animals
• CD8-Positive T-Lymphocytes
• Cancer Vaccines (therapeutic use)
• Interferon-gamma (metabolism)
• Emulsions (metabolism, pharmacology)
• Leukocytes, Mononuclear (metabolism)
• WT1 Proteins
• Neoplasms (metabolism)
• Peptides
• T-Lymphocytes, Cytotoxic
• Mice, Transgenic
• Tumor Microenvironment