Author:
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
Abstract
Abstract
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.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Immunology,Immunology and Allergy
Cited by
9 articles.
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