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BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Leukemia | Research

Enhanced antitumor activity of a novel, oral, helper epitope-containing WT1 protein vaccine in a model of murine leukemia

Authors: Hikaru Minagawa, Yoshiko Hashii, Hiroko Nakajima, Fumihiro Fujiki, Soyoko Morimoto, Jun Nakata, Toshiro Shirakawa, Takane Katayama, Akihiro Tsuboi, Keiichi Ozono

Published in: BMC Cancer | Issue 1/2023

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Abstract

Background

A Wilms’ tumor 1 (WT1) oral vaccine, Bifidobacterium longum (B. longum) 420, in which the bacterium is used as a vector for WT1 protein, triggers immune responses through cellular immunity consisting of cytotoxic T lymphocytes (CTLs) and other immunocompetent cells (e.g., helper T cells). We developed a novel, oral, helper epitope-containing WT1 protein vaccine (B. longum 2656) to examine whether or not B. longum 420/2656 combination further accelerates the CD4+ T cell help-enhanced antitumor activity in a model of murine leukemia.

Methods

C1498-murine WT1—a genetically-engineered, murine leukemia cell line to express murine WT1—was used as tumor cell. Female C57BL/6 J mice were allocated to the B. longum 420, 2656, and 420/2656 combination groups. The day of subcutaneous inoculation of tumor cells was considered as day 0, and successful engraftment was verified on day 7. The oral administration of the vaccine by gavage was initiated on day 8. Tumor volume, the frequency and phenotypes of WT1-specific CTLs in CD8+ T cells in peripheral blood (PB) and tumor-infiltrating lymphocytes (TILs), as well as the proportion of interferon-gamma (INF-γ)-producing CD3+CD4+ T cells pulsed with WT135–52 peptide in splenocytes and TILs were determined.

Results

Tumor volume was significantly smaller (p < 0.01) in the B. longum 420/2656 combination group than in the B. longum 420 group on day 24. WT1-specific CTL frequency in CD8+ T cells in PB was significantly greater in the B. longum 420/2656 combination group than in the B. longum 420 group at weeks 4 (p < 0.05) and 6 (p < 0.01). The proportion of WT1-specific, effector memory CTLs in PB increased significantly in the B. longum 420/2656 combination group than in the B. longum 420 group at weeks 4 and 6 (p < 0.05 each). WT1-specific CTL frequency in intratumoral CD8+ T cells and the proportion of IFN-γ-producing CD3+CD4+ T cells in intratumoral CD4+ T cells increased significantly (p < 0.05 each) in the B. longum 420/2656 combination group than in the 420 group.

Conclusions

B. longum 420/2656 combination further accelerated antitumor activity that relies on WT1-specific CTLs in the tumor compared with B. longum 420.
Literature
1.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.CrossRefPubMedPubMedCentral
2.
Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.CrossRefPubMedPubMedCentral
3.
Oji Y, Ogawa H, Tamaki H, Oka Y, Tsuboi A, Kim EH, et al. Expression of the Wilms' tumor gene WT1 in solid tumors and its involvement in tumor cell growth. Jpn J Cancer Res. 1999;90:194–204.CrossRefPubMedPubMedCentral
4.
Sugiyama H. WT1 (Wilms' tumor gene 1): biology and cancer immunotherapy. Jpn J Clin Oncol. 2010;40:377–87.CrossRefPubMed
5.
Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, et al. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15:5323–37.CrossRefPubMedPubMedCentral
6.
Saxena M, van der Burg SH, Melief CJM, Bhardwaj N. Therapeutic cancer vaccines. Nat Rev Cancer. 2021;21:360–78.CrossRefPubMed
7.
Oka Y, Udaka K, Tsuboi A, Elisseeva OA, Ogawa H, Aozasa K, et al. Cancer immunotherapy targeting Wilms' tumor gene WT1 product. J Immunol. 2000;164:1873–80.CrossRefPubMed
8.
Hashii Y, Sato-Miyashita E, Matsumura R, Kusuki S, Yoshida H, Ohta H, et al. WT1 peptide vaccination following allogeneic stem cell transplantation in pediatric leukemic patients with high risk for relapse: successful maintenance of durable remission. Leukemia. 2012;26:530–2.CrossRefPubMed
9.
Izumoto S, Tsuboi A, Oka Y, Suzuki T, Hashiba T, Kagawa N, et al. Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J Neurosurg. 2008;108:963–71.CrossRefPubMed
10.
Ruiz L, Delgado S, Ruas-Madiedo P, Sánchez B, Margolles A. Bifidobacteria and their molecular communication with the immune system. Front Microbiol. 2017;8:2345.CrossRefPubMedPubMedCentral
11.
Kitagawa K, Gonoi R, Tatsumi M, Kadowaki M, Katayama T, Hashii Y, et al. Preclinical development of a WT1 oral cancer vaccine using a bacterial vector to treat castration-resistant prostate cancer. Mol Cancer Ther. 2019;18:980–90.CrossRefPubMed
12.
Borst J, Ahrends T, Babala N, Melief CJM, Kastenmuller W. CD4+ T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 2018;18:635–47.CrossRefPubMed
13.
Ahrends T, Busselaar J, Severson TM, Babala N, de Vries E, Bovens A, et al. CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities. Nat Commun. 2019;10:5531.CrossRefPubMedPubMedCentral
14.
Kitagawa K, Oda T, Saito H, Araki A, Gonoi R, Shigemura K, et al. Development of oral cancer vaccine using recombinant Bifidobacterium displaying Wilms' tumor 1 protein. Cancer Immunol Immunother. 2017;66:787–98.CrossRefPubMed
15.
Nakajima H, Nakata J, Imafuku K, Hayashibara H, Isokawa K, Udaka K, et al. Identification of mouse helper epitopes for WT1-specific CD4+ T cells. Cancer Immunol Immunother. 2021;70:3323–35.CrossRefPubMed
16.
Nakagawa N, Hashii Y, Kayama H, Okumura R, Nakajima H, Minagawa H, et al. An oral WT1 protein vaccine composed of WT1-anchored, genetically engineered Bifidobacterium longum allows for intestinal immunity in mice with acute myeloid leukemia. Cancer Immunol Immunother. 2023;72:39–53.CrossRefPubMed
17.
Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:541–50.CrossRefPubMedPubMedCentral
18.
19.
Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35(Suppl):S185–S98.CrossRefPubMed
20.
Baghban R, Roshangar L, Jahanban-Esfahlan R, Seidi K, Ebrahimi-Kalan A, Jaymand M, et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal. 2020;18:59.CrossRefPubMedPubMedCentral
21.
22.
Benavente S, Sánchez-García A, Naches S, Me LL, Lorente J. Therapy-induced modulation of the tumor microenvironment: new opportunities for cancer therapies. Front Oncol. 2020;10:582884.CrossRefPubMedPubMedCentral
23.
Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.
24.
25.
Abd Hamid M, Yao X, Waugh C, Rosendo-Machado S, Li C, Rostron T, et al. Defective interferon gamma production by tumor-specific CD8+ T cells is associated with 5'methylcytosine-guanine hypermethylation of interferon gamma promoter. Front Immunol. 2020;11:310.CrossRefPubMedPubMedCentral
26.
Yokota C, Nakata J, Takano K, Nakajima H, Hayashibara H, Minagawa H, et al. Distinct difference in tumor-infiltrating immune cells between Wilms' tumor gene 1 peptide vaccine and anti-programmed cell death-1 antibody therapies. Neurooncol Adv. 2021;3:vdab091.PubMedPubMedCentral
27.
Wang JC, Livingstone AM. Cutting edge: CD4+ T cell help can be essential for primary CD8+ T cell responses in vivo. J Immunol. 2003;171:6339–43.CrossRefPubMed
28.
Ahrends T, Spanjaard A, Pilzecker B, Babala N, Bovens A, Xiao Y, et al. CD4+ T cell help confers a cytotoxic T cell effector program including coinhibitory receptor downregulation and increased tissue invasiveness. Immunity. 2017;47:848–61.e5.CrossRef
Metadata
Title
Enhanced antitumor activity of a novel, oral, helper epitope-containing WT1 protein vaccine in a model of murine leukemia
Authors
Hikaru Minagawa
Yoshiko Hashii
Hiroko Nakajima
Fumihiro Fujiki
Soyoko Morimoto
Jun Nakata
Toshiro Shirakawa
Takane Katayama
Akihiro Tsuboi
Keiichi Ozono
Publication date
01-12-2023
Publisher
BioMed Central
Keyword
Leukemia
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-10547-5

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