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

BACKGROUND: This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor 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...

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Detalles Bibliográficos
Autores principales: Nakajima, Masao, Hazama, Shoichi, Tamada, Koji, Udaka, Keiko, Kouki, Yasunobu, Uematsu, Toshinari, Arima, Hideki, Saito, Akira, Doi, Shun, Matsui, Hiroto, Shindo, Yoshitaro, Matsukuma, Satoshi, Kanekiyo, Shinsuke, Tokumitsu, Yukio, Tomochika, Shinobu, Iida, Michihisa, Yoshida, Shin, Nakagami, Yuki, Suzuki, Nobuaki, Takeda, Shigeru, Yamamoto, Shigeru, Yoshino, Shigefumi, Ueno, Tomio, Nagano, Hiroaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Clinical Trial Report
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347520/
https://www.ncbi.nlm.nih.gov/pubmed/32219501
http://dx.doi.org/10.1007/s00262-020-02518-7
Descripción
Sumario:BACKGROUND: This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-020-02518-7) contains supplementary material, which is available to authorized users.

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