Exploration of a new biomarker for companion diagnostics of HPV-targeting cancer immunotherapy

• Project/Area Number: 18K09303
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Nihon University
• Principal Investigator: KAWANA Kei 日本大学, 医学部, 教授 (60311627)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 子宮頸癌 / 子宮頸部上皮内腫瘍 / ヒトパピローマウイルス（HPV） / 免疫療法 / コンパニオン診断 / HPVE7発現 / ヒトパピローマウイルス / HPV18 / HPV E6/E7 / 腺癌 / 粘膜免疫療法 / HPVE7発現乳酸菌製剤 / HPV / 癌免疫療法 / CIN治療薬 / 分子標的治療 / 子宮頸部高度上皮内腫瘍（CIN2-3） / E7発現乳酸菌 / 医師主導治験 / 第I/II相臨床試験 / E7発現量 / E7発現乳酸菌製剤

Outline of Final Research Achievements

In this study, we aimed to search for biomarkers that would serve as companion diagnostics for the HPV16E7-expressing lactobacillus vaccine that is being developed as a cancer immunotherapy targeting HPV16 onco-protein E7. We thought that HPV16E7 expression level in the exfoliated cells collected from high-grade cervical intraepithelial neoplasia CIN2-3 could be the most promising marker. We here established an assay system to measure HPV16E7 expression in the lesion using RT-PCR. We will examine the usefulness of HPV16E7 expression as a companion diagnosis in ongoing investigator-initiated clinical trials.

Academic Significance and Societal Importance of the Research Achievements

高度子宮頸部上皮内腫瘍CIN2-3に対する薬物療法は未だに未開発のアンメットニーズである。HPVには抗ウイルス薬は存在せず、現在、治療薬開発で最も有力な候補は免疫療法である。世界的に開発が進んでいる。免疫療法では有効例と無効例の差が大きい特徴があり、有効例選択の診断ツールの必要性が高く、その候補であるコンパニオン診断の測定系を開発したことは有意義である。

Research Products

• [Journal Article] A low preoperative albumin-to-globulin ratio is a negative prognostic factor in patients with surgically treated cervical cancer (2021)
  • Author(s): Kawata Akira、Taguchi Ayumi、Baba Satoshi、Miyamoto Yuichiro、Tanikawa Michihiro、Sone Kenbun、Tsuruga Tetsushi、Mori Mayuyo、Oda Katsutoshi、Kawana Kei、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: International Journal of Clinical Oncology Volume: 26 Issue: 5 Pages: 980-985
  • DOI: 10.1007/s10147-021-01861-8
  • Peer Reviewed / Open Access
• [Journal Article] A placebo-controlled, double-blind randomized (Phase IIB) trial of oral aministration with HPV16 E7-expressing Lactobacillus, GLBL101c, for the treatment of cervical intraepithelial neoplasia grade 2 (CIN2) (2021)
  • Author(s): Ikeda Y,Adachi K,Tomio K, Eguchi-Kojima S,Tsuruga T, Uchino-Mori M,Taguchi A,Komatsu A,Nagamatsu T, Oda K, Kawana-Tachikawa A, Uemura Y,Igimi S,Osuga Y,Fujii T, Kawana K
  • Journal Title: vaccines Volume: 未定
  • Peer Reviewed / Open Access
• [Journal Article] Multistate markov model to predict the prognosis of high-risk human papillomavirus-related cervical lesions (2020)
  • Author(s): Taguchi A, Hara K, Tomio J, Kawana K, Tanaka T, Baba S, Kawata A, Eguchi S, Tsuruga T, Mori M, Adachi K, Nagamatsu T, Oda K, Yasugi T, Osuga Y, Fujii T.
  • Journal Title: Cancers (Basel). Volume: 12 Issue: 2 Pages: 1-15
  • DOI: 10.3390/cancers12020270
  • Peer Reviewed / Open Access
• [Journal Article] Reconstructed uterine length is critical for the prevention of cervical stenosis following abdominal trachelectomy in cervical cancer patients (2020)
  • Author(s): Nakajima T, Kasuga A, Hara-Yamashita A, Ikeda Y, Asai-Sato M, Nakao T, Hayashi C, Takeya C, Adachi K, Tsuruga T, Matsumoto Y, Arimoto T, Nagamatsu T, Oda K, Komatsu A, Chishima F, Osuga Y, Fujii T, Kawana K,
  • Journal Title: J Obstet Gynecol Res, Volume: 46 Issue: 2 Pages: 328
  • DOI: 10.1111/jog.14153
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of survival between primary debulking surgery and neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in phase III randomized trial (2020)
  • Author(s): Onda T, Satoh T, Ogawa G, Saito T, Kasamatsu T, Nakanishi T, Mizutani T, Takehara K, Okamoto A, Ushijima K, Kobayashi H, Kawana K, Yokota H, Takano M, Kanao H, Watanabe Y, Yamamoto K, Yaegashi N, Kamura T, Yoshikawa H, Japan Clinical Oncology Group,
  • Journal Title: Eur J Cancer Volume: 130 Pages: 114-125
  • DOI: 10.1016/j.ejca.2020.02.020
  • Peer Reviewed / Open Access
• [Journal Article] Impact of additional risk factors on the incidence of preterm delivery among pregnant women diagnosed with short cervix (2020)
  • Author(s): Samejima Taiki、Nagamatsu Takeshi、Iriyama Takayuki、Nakayama Toshio、Seyama Takahiro、Sayama Seisuke、Kumasawa Keiichi、Komatsu Atsushi、Kawana Kei、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Taiwanese Journal of Obstetrics and Gynecology Volume: 59 Issue: 2 Pages: 195-199
  • DOI: 10.1016/j.tjog.2020.01.005
  • Peer Reviewed / Open Access
• [Journal Article] Differential expression of human papillomavirus 16-, 18-, 52-, and 58-derived transcripts in cervical intraepithelial neoplasia (2020)
  • Author(s): Baba S, Taguchi A, Kawata A, Hara K, Eguchi S, Mori M, Adachi K, Mori S, Iwata T, Mitsuhashi A, Maeda D, Komatsu A, Nagamatsu T, Oda K, Kukimoto I, Osuga Y, Fujii T, Kawana K.
  • Journal Title: Virol J Volume: 17 Issue: 1 Pages: 32-32
  • DOI: 10.1186/s12985-020-01306-0
  • NAID: 120007089054
  • Peer Reviewed / Open Access
• [Journal Article] Use of Cap Analysis Gene Expression to detect human papillomavirus promoter activity patterns at different disease stages (2020)
  • Author(s): Taguchi A, Nagasaka K, Plessy C, Nakamura H, Kawata Y, Kato S, Hashimoto K, Nagamatsu T, Oda K, Kukimoto I, Kawana K, Carninci P, Osuga Y, Fujii T.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 17991-17991
  • DOI: 10.1038/s41598-020-75133-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Safety and efficacy of mucosal immunotherapy using human papillomavirus (HPV) type 16 E7-expressing Lactobacillus-based vaccine for the treatment of high-grade squamous intraepithelial lesion (HSIL): the study protocol of a randomized placebo-controlled clinical trial (MILACLE study), (2019)
  • Author(s): Ikeda Y, Uemura Y, Asai-Sato M, Nakao T, Nakajima T, Iwata T, Akiyama A, Satoh T, Yahata H, Kato K, Maeda D, Aoki D, Kawana K
  • Journal Title: Jap J Clin Oncol, Volume: 49(9) Issue: 9 Pages: 877-880
  • DOI: 10.1093/jjco/hyz095
  • Peer Reviewed / Open Access
• [Journal Article] Radiation therapy for vaginal cancer in complete uterine prolapse with intrauterine adhesion: a case report. (2019)
  • Author(s): Ishibashi N, Maebayashi T, Asai-Sato M, Kawana K, Okada M
  • Journal Title: BMC Womens Health. Volume: 19(69) Issue: 1 Pages: 69-82
  • DOI: 10.1186/s12905-019-0767-5
  • Peer Reviewed / Open Access
• [Journal Article] Development and evaluation of a cervical cancer screening system in Cambodia: A collaborative project of the Cambodian Society of Gynecology and Obstetrics and Japan Society of Obstetrics and Gynecology. (2019)
  • Author(s): 4.Ueda Y, Kawana K, Yanaihara N, Banno K, Chhit M, Uy K, Kruy L, Sann CS, Ishioka-Kanda M, Akaba H, Matsumoto Y, Fujita N, Yano T, Koum K, Okamoto A, Kimura T,
  • Journal Title: J Obstet Gynaecol Res Volume: 45(7) Issue: 7 Pages: 1260-1267
  • DOI: 10.1111/jog.13968
  • Peer Reviewed / Open Access
• [Journal Article] Neoadjuvant chemotherapy with taxane and platinum followed by radical hysterectomy for stage IB2-IIB cervical cancer: Impact of histology type on survival. (2019)
  • Author(s): Matsuo K, Shimada M, Yamaguchi S, Kigawa J, Tokunaga H, Tabata T, Kodama J, Kawana K, Mikami M, Sugiyama T.
  • Journal Title: Journal of Clinical Medicine Volume: 30: 8(2) Issue: 2 Pages: 156-169
  • DOI: 10.3390/jcm8020156
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutic significance of targeting survivin in cervical cancer and possibility of combination therapy with TRAIL (2018)
  • Author(s): Nakamura H, Taguchi A, Kawana K, Baba S, Kawata A, Yoshida M, Fujimoto A, Ogishima J, Sato M, Inoue T, Nishida H, Furuya H, Yamashita A, Eguchi S, Tomio K, Mori-Uchino M, Adachi K, Arimoto T, Wada-Hiraike O, Oda K, Nagamatsu T, Osuga Y, Fujii T
  • Journal Title: Oncotarget Volume: 9 Issue: 17 Pages: 13451
  • DOI: 10.18632/oncotarget.24413
  • Peer Reviewed / Open Access
• [Journal Article] Optimization of human papillomavirus (HPV) type 16 E7-expressing lactobacillus-based vaccine for induction of mucosal E7-specific IFNγ-producing cells (2018)
  • Author(s): Komatsu Atsushi、Igimi Shizunobu、Kawana Kei
  • Journal Title: Vaccine Volume: 36 Issue: 24 Pages: 3423-3426
  • DOI: 10.1016/j.vaccine.2018.05.009
  • Peer Reviewed / Open Access
• [Journal Article] The oncogene KRAS promotes cancer cell dissemination by stabilizing spheroid formation via the MEK pathway (2018)
  • Author(s): Ogishima J, Taguchi A, Kawata A, Kawana K, Yoshida M, Yoshimatsu Y, Sato M, Nakamura H, Kawata Y, Nishijima A, Fujimoto A, Tomio K, Adachi K, Nagamatsu T, Oda K, Kiyono T, Osuga Y, Fujii T
  • Journal Title: BMC Cancer Volume: 18 Issue: 1 Pages: 1-13
  • DOI: 10.1186/s12885-018-4922-4
  • URL: https://pure.teikyo.jp/en/publications/2b9a0bfc-174d-4ad5-9cb0-5a3ab2d5d9b0
  • Peer Reviewed / Open Access
• [Presentation] 専攻医教育プログラム HPVワクチンの知識アップデート (2020)
  • Author(s): 川名 敬
  • Organizer: 日本産科婦人科学会学術講演会
• [Presentation] シンポジウム HPV関連癌の病理と臨床―臓器横断的視点で― 子宮頸部から発生するHPV関連発癌のメカニズムとその治療戦略 (2020)
  • Author(s): 川名 敬
  • Organizer: 日本臨床細胞学会 春季大会
• [Presentation] 教育セミナー 世界中で安全性が報告されているHPVワクチンをどうして止めているのか？ (2020)
  • Author(s): 川名 敬
  • Organizer: 日本小児科学会学術集会
• [Presentation] ワークショップ 日本の小中高校におけるがん教育の現状～ HPVワクチンと子宮頸がんを題材にして (2020)
  • Author(s): 川名 敬
  • Organizer: 日本思春期学会
• [Presentation] 子宮頸癌の発癌メカニズムから考えた予防、治療～リプロダクティブヘルスを守るために (2020)
  • Author(s): 川名 敬
  • Organizer: 大阪女性医療フォーラム
• [Presentation] HPVワクチン及び新経口ワクチンにおける最新情報 (2020)
  • Author(s): 川名 敬
  • Organizer: 東京産婦人科医会・東京産科婦人科学会合同研修会
• [Presentation] 特別講演HPVワクチンの国内外の最新情報とHPV標的CIN2-3治療薬の開発 (2020)
  • Author(s): 川名 敬
  • Organizer: 東京産科婦人科学会例会
• [Presentation] シンポジウム２性感染症ワクチンの未来HPVワクチンで子宮頸がんの撲滅は可能か (2020)
  • Author(s): 川名 敬
  • Organizer: 日本性感染症学会
• [Presentation] A novel HPV-targeting mucosal immunotherapy for treatment of cervical neoplasia: Phase I/II clinical trials, (2019)
  • Author(s): kei kawana
  • Organizer: The 34th Annual Meeting of the Japanese Society forImmunology of Reproduction,
  • Int'l Joint Research / Invited
• [Presentation] ヒトパピローマウイルス(HPV)の発癌過程に基づく癌治療の創薬開発 (2019)
  • Author(s): 川名 敬
  • Organizer: 第57回日本癌治療学会
  • Invited
• [Presentation] 「HPV ワクチンを再開するためにどうしたらよいのか？」 (2019)
  • Author(s): 川名 敬
  • Organizer: 関東連合産科婦人科学会
  • Invited
• [Presentation] HPV ワクチン問題をどう打開するべきか～次の一手は？ (2019)
  • Author(s): 川名 敬
  • Organizer: 日本性感染症学会 第32回学術大会
  • Invited
• [Presentation] 産婦人科診療と性行為感染～梅毒・子宮頸部腫瘍の診療に役立つ知識のアップデート (2019)
  • Author(s): 川名 敬
  • Organizer: 第96回埼玉産科婦人科学会・産婦人科医会後期学術集会
  • Invited
• [Presentation] 子宮頸癌の発癌メカニズムに基づく創薬開発と産婦人科感染症 (2019)
  • Author(s): 川名 敬
  • Organizer: 第６回島根産婦人科フォーラム
  • Invited
• [Presentation] HPVと子宮頸癌 ～クリニカルクエスチョンから考えられた新しい治療戦略 (2019)
  • Author(s): 川名 敬
  • Organizer: 第13回千葉産婦人科臨床問題研究会
  • Invited
• [Presentation] 女性の健康を守るために～今の日本で子宮頸癌予防に必要なことは (2019)
  • Author(s): 川名 敬
  • Organizer: 北海道女性医療セミナー
  • Invited
• [Presentation] 婦人科癌に対する創薬研究 : 粘膜免疫療法と癌幹細胞標的療法 (2018)
  • Author(s): 川名 敬
  • Organizer: 第59回日本婦人科腫瘍学会学術講演会
  • Invited
• [Presentation] 子宮頸癌/HPVワクチンの現状と課題 HPVワクチンの今取り組むべきこと 海外と日本の違い (2018)
  • Author(s): 川名 敬
  • Organizer: 日本性感染症学会 第31回学術大会
  • Invited
• [Book] Current Human Cell Research and Applications Vol. 5 “Molecular Diagnosis and Targeting for Gynecologic Malignancy” (2021)
  • Author(s): Seiji Isonisho/Yoshihiro Kikuchi
  • Total Pages: 165
  • Publisher: Springer Nature
  • ISBN: 9789813360129