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CYT001の特定臨床研究(YNP01試験)結果の論文掲載のお知らせ

特定臨床研究「進行・再発固形癌に対するHSP70由来ペプチド+GPC3由来ペプチド+IMP321+Hiltonolの複合免疫療法としての第Ⅰ相臨床試験 (YNP01)」(研究責任者:山口大学大学院医学系研究科消化器・腫瘍外科学 永野浩昭教授、研究立案者:山口大学医学部先端がん治療開発学 硲彰一教授、共同研究:サイトリミック株式会社)の試験結果がCancer Immunology, Immunotherapy誌に掲載されました(オンライン版)。
YNP01試験は進行・再発固形癌(食道癌、膵癌、肝癌、胃癌、直腸癌、大腸癌)患者を対象とし、HSP70由来ペプチド+GPC3由来ペプチド+IMP321+Hiltonol (CYT001)を初めてヒトに投与する臨床試験です。AIを用いたペプチド予測が複数のHLA型で免疫誘導するペプチドの発見を可能とし、Poly-ICLCとLAG-3Igの組み合わせアジュバントがマルチHLAペプチドワクチンの抗腫瘍効果を相乗的に高めると期待されます。
本試験は3人の患者コホートでの用量漸増試験であり、推奨用量で11人の患者が登録されました。約70%の症例で各々のペプチドに対するCTL反応が得られ、特に推奨用量では半数以上が1ヶ月で強いCTL反応を示しました。更に、推奨用量では、末梢血中で疲弊マーカー(TIM3)を発現したリンパ球(TIM3+CD4 T細胞)が有意に減少したこと、11症例中5例で生存期間が18ヶ月以上であったことなどが報告されています。
なお、本試験で導かれた推奨投与量が医師主導Phase1b治験(CRESCENT1)の投与量設定に用いられています。
サイトリミック株式会社は、本試験で得られた結果・知見に基づき、医療機関との共同研究を通してCYT001の実用化を進めてまいります。
Abstract titles, authors and abstracts are:
Title: A phase I study of multi-HLA binding peptides derived from heat shock protein 70/glypican-3 and a novel combination adjuvant of hLAG-3Ig and Poly-ICLC for patients with metastatic gastrointestinal cancers: YNP01 trial
Authors: Masao Nakajima1, Shoichi Hazama2, Koji Tamada3, Keiko Udaka4, Yasunari Kouki5, Toshinari Uematsu5, Hideki Arima5, Akira Saito6, Tomoya Miyakawa7, Shun Doi8, Hiroto Matsui1, Yoshitaro Shindo1, Shinsuke Kanekiyo1, Yukio Tokumitsu1, Shinobu Tomochika1, Michihisa Iida1, Shin Yoshida1, Nobuaki Suzuki1, Shigeru Takeda1, Shigefumi Yoshino9, Tomio Ueno10, Hiroaki Nagano1
  1. Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
  2. Department of Translational Research and Developmental Therapeutics against Cancer, Yamaguchi University School of Medicine, Ube, Japan
  3. Department of Immunology, Yamaguchi University Graduate School of Medicine, Ube, Japan
  4. Department of Immunology, Kochi Medical School, Nankoku, Japan
  5. Department of Pharmacy, Yamaguchi University Hospital, Ube, Japan
  6. Department of Pathology, Tokyo Medical University, Tokyo, Japan
  7. NEC Corporation, Tokyo, Japan
  8. CYTLIMIC Inc., Tokyo, Japan
  9. Oncology Center, Yamaguchi University Hospital, Ube, Japan
  10. Department of Digestive Surgery, Kawasaki University School of Medicine, Kurashiki, Japan
 
 
Abstract:
BACKGROUND: This phase I study aimed to evaluate the safety, peptide-specific immune responses, and antitumor effects of a novel vaccination therapy comprising multi-HLA-binding heat shock protein (HSP) 70/ glypican-3 (GPC3) peptides and a novel adjuvant combination of hLAG-3Ig and Poly-ICLC against metastatic gastrointestinal cancers.
METHODS: HSP70/GPC3 peptides with high binding affinities for three HLA types (A*24:02, A*02:01, and A*02:06) were identified with our peptide prediction system. The peptides were intradermally administered with combined adjuvants on a weekly basis. This study was a phase I dose-escalation clinical trial, which was carried out in a three patients’ cohort; in total, 11 patients were enrolled for the recommended dose.
RESULTS: Seventeen patients received this vaccination therapy without dose-limiting toxicity. All treatment-related adverse events were of grades 1 to 2. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 (64.7%) and 13 (76.5%) cases, respectively, regardless of the HLA type. Serum tumor marker levels were decreased in 10 cases (58.8%). Immunological analysis using PBMCs indicated that patients receiving dose level 3 presented with significantly reduced T cell immunoglobulin and mucin-domain containing-3 (TIM3)-expressing CD4+ T cells after one course of treatment. PD-1 or TIM3-expressing CD4+ T cells and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)-expressing CD8+ T cells in PBMCs before vaccination were negative predictive factors for survival.
CONCLUSIONS: This novel peptide vaccination therapy was safe for patients with metastatic gastrointestinal cancers.
Reference: Cancer Immunology, Immunotherapy, (On-line Article)
Download: (https://link.springer.com/article/10.1007/s00262-020-02518-7)
YNP01試験:進行・再発固形癌に対するHSP70由来ペプチド+GPC3由来ペプチド+IMP321+Hiltonolの複合免疫療法としての第I相臨床試験、特定臨床研究公表日:2019年4月26日, jRCT登録:jRCTs061180058 (https://jrct.niph.go.jp/latest-detail/jRCTs061180058)

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