PMID- 36138335
OWN - NLM
STAT- MEDLINE
DCOM- 20230126
LR  - 20230201
IS  - 1699-3055 (Electronic)
IS  - 1699-048X (Print)
IS  - 1699-048X (Linking)
VI  - 25
IP  - 2
DP  - 2023 Feb
TI  - 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.
PG  - 396-407
LID - 10.1007/s12094-022-02946-0 [doi]
AB  - 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.
CI  - (c) 2022. The Author(s).
FAU - Suginobe, Natsuko
AU  - Suginobe N
AD  - Sumitomo Pharma Co., Ltd., 3-1-98, Kasugade Naka, Konohana-ku, Osaka, 554-0022, 
      Japan.
FAU - Nakamura, Megumi
AU  - Nakamura M
AD  - Sumitomo Pharma Co., Ltd., 3-1-98, Kasugade Naka, Konohana-ku, Osaka, 554-0022, 
      Japan.
FAU - Takanashi, Yosuke
AU  - Takanashi Y
AD  - Sumitomo Pharma Co., Ltd., 3-1-98, Kasugade Naka, Konohana-ku, Osaka, 554-0022, 
      Japan.
FAU - Ban, Hitoshi
AU  - Ban H
AD  - Sumitomo Pharma Co., Ltd., 3-1-98, Kasugade Naka, Konohana-ku, Osaka, 554-0022, 
      Japan.
FAU - Gotoh, Masashi
AU  - Gotoh M
AUID- ORCID: 0000-0003-1003-5074
AD  - Sumitomo Pharma Co., Ltd., 3-1-98, Kasugade Naka, Konohana-ku, Osaka, 554-0022, 
      Japan. masashi.goto@sumitomo-pharma.co.jp.
LA  - eng
PT  - Journal Article
DEP - 20220923
PL  - Italy
TA  - Clin Transl Oncol
JT  - Clinical & translational oncology : official publication of the Federation of 
      Spanish Oncology Societies and of the National Cancer Institute of Mexico
JID - 101247119
RN  - 0 (Cancer Vaccines)
RN  - 82115-62-6 (Interferon-gamma)
RN  - 0 (Emulsions)
RN  - 0 (WT1 Proteins)
RN  - 0 (Peptides)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - CD8-Positive T-Lymphocytes
MH  - *Cancer Vaccines/therapeutic use
MH  - Interferon-gamma/metabolism
MH  - Emulsions/metabolism/pharmacology
MH  - Leukocytes, Mononuclear/metabolism
MH  - WT1 Proteins
MH  - *Neoplasms/metabolism
MH  - Peptides
MH  - T-Lymphocytes, Cytotoxic
MH  - Mice, Transgenic
MH  - Tumor Microenvironment
PMC - PMC9510518
OTO - NOTNLM
OT  - Adegramotide
OT  - Cytotoxic T lymphocytes
OT  - DSP-7888
OT  - Helper T lymphocytes
OT  - Immune checkpoint inhibitor
OT  - Mechanism of action
OT  - Nelatimotide
OT  - Therapeutic cancer vaccine
OT  - Tumor microenvironment
OT  - Wilms' tumor 1 (WT1)
COIS- The authors are salaried employees of Sumitomo Pharma Co., Ltd., the maker of 
      DSP-7888 Emulsion.
EDAT- 2022/09/23 06:00
MHDA- 2023/01/27 06:00
PMCR- 2022/09/23
CRDT- 2022/09/22 23:36
PHST- 2022/05/17 00:00 [received]
PHST- 2022/09/01 00:00 [accepted]
PHST- 2022/09/23 06:00 [pubmed]
PHST- 2023/01/27 06:00 [medline]
PHST- 2022/09/22 23:36 [entrez]
PHST- 2022/09/23 00:00 [pmc-release]
AID - 10.1007/s12094-022-02946-0 [pii]
AID - 2946 [pii]
AID - 10.1007/s12094-022-02946-0 [doi]
PST - ppublish
SO  - Clin Transl Oncol. 2023 Feb;25(2):396-407. doi: 10.1007/s12094-022-02946-0. Epub 
      2022 Sep 23.