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Recently, the aggressive intervention of multidisciplinary therapy has resulted in improving the life prognosis of pediatric solid tumors. However, in the pediatric patients with metastatic or refractory solid tumors, the prognosis remains poor. Additionally, various critical, late complications could continue to occur. Therefore, the development of novel, effective therapy is urgently required. Immunotherapy could be the one of effective therapeutic strategy for pediatric solid tumors. Actually, the KOC1, FOXM1, and KIF20A might be capable of being an ideal target of anticancer immunotherapy against pediatric solid tumors that highly had expression of these cancer antigens. In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of NCCV cocktail 1 vaccine, a cocktail of cancer peptides derived from KOC1, FOXM1, and KIF20A, in patients with pediatric solid tumors. Experimental Design: Twelve patients with refractory pediatric solid tumors, including 3 patients with neuroblastoma, 2 patients with Ewing’s sarcoma, 5 patients with rhabdomyosarcoma, and 2 patients with osteosarcoma, underwent NCCV cocktail 1 vaccination (intradermal injections every a week). In 9 enrolled patients, the histologic expression of KOC1, FOXM1, and KIF20A before vaccination were evaluated using tissue specimen obtained from biopsy or surgery. The primary endpoint was the safety of NCCV cocktail 1 vaccination. The secondary endpoints were immune response, as measured by in vivo and in vitro interferon (IFN)-r enzyme-linked immunospot (ELISPOT) assay and Dextramer assay, and the clinical outcomes of tumor response and progression free survival (PFS).Results:No dose-limiting toxicity (DLT) was observed in this trial, and we suggested that NCCV cocktail 1 vaccination was well-tolerated. Of nine patients, 6 patients (66.7%), 6 patients (66.7%), and 7 patients (77.8%), exhibited positive expression of KOC1, FOXM1, and KIF20A before vaccination, respectively. Of eleven patients, 4 patients (36.4%), 8 patients (72.7%), and 5 patients (45.5%) were induced peptide-specific CTL response of KOC, FOXM1, and KIF20A by NCCV cocktail 1 vaccine, respectively. Also, 4 patients showed stable disease after 8 weeks, and 2 patients showed during of remission for more than 11 months after second complete remission. Additionally, patients with high peptide-specific CTL frequencies of all KOC, FOXM1, and KIF20A (n=4) had better PFS than those with low frequencies (n=7) by Kaplan-Meier analysis (log-rank test, P =0.019). By Cox proportional hazard models, univariate and multivariate analysis indicated that only induction of peptide specific CTL in all of these three antigens was independent factor related to PFS (P = 0.039; HR = 5.60; 95% CI 1.09-28.91, P = 0.050; HR = 6.00; 95% CI 1.00-36.32, respectively). Conclusions:The results of this trial demonstrated that the NCCV cocktail 1 vaccine was safe and had ability to induce some degree of immune response, which could result in the benefit for preventing the recurrence of pediatric solid tumors, especially after a second complete remission. Citation Format: Yu Akazawa, Ako Hosono, Toshiaki Yoshikawa, Hide Kaneda, Junichi Hara, Yoshiaki Kinoshita, Kenichi Kohashi, Atsushi Manabe, Yoko Shioda, Kayoko Shoda, Manami Shimomura, Shoichi Mizuno, Yasunari Nakamoto, Tetsuya Nakatsura. Phase I study of vaccine therapy with a cocktail of peptides for pediatric patients with refractory solid tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A001.

Purpose: Heat shock protein 105 (HSP105) is overexpressed in a variety of human cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We identified HLA-A24 or A2-restricted HSP105 peptides that can induce HSP105 peptide-specific cytotoxic T lymphocytes (CTLs) (EP1536006, JP5112615, JP5291641, US9,404,925) and curried out a phase I clinical trial of HLA-A24 or A2-restricted HSP105 peptide vaccine in patients with CRC or EC (UMIN ID000017809). In this study, we aimed to demonstrate the immunological efficacy of the novel vaccine. Experimental design: 30 patients (HLA-A24 group; 15 patients, HLA-A2 group; 15 patients) with advanced CRC or EC were enrolled. Two types of vaccine (A24-1 and A24-7 or A2-7 and A2-12) were administered into the patients, matching HLA-types. Immunological responses were analyzed by ex vivo and in vitro IFN-γ ELISPOT assay using peripheral blood mononuclear cells before and after vaccination, and cytokines produced by HSP105-specific CTLs were measured by Cytometric Bead Array assay. We also analyzed the correlation between immunological responses and prognosis. Result: HSP105 peptide vaccines induced HSP105 peptide-specific CTLs in 15 of 30 patients. In HLA-A24 group, there were 7 patients with the induction only in ex vivo and almost all patients (n=13) showed skin reactions of vaccine sites. By contrast, in HLA-A2 group, there were 4 patients with the induction in ex vivo and 6 patients in in vitro, respectively, and only 6 patients with skin reactions of vaccine sites. In all patients, the existence of skin reaction correlated with the induction in ex vivo (p Citation Format: Yasuhiro Shimizu, Toshiaki Yoshikawa, Kojima Takashi, Kayoko Shoda, Kazuto Nosaka, Shoichi Mizuno, Satoshi Wada, Yuki Fujimoto, Tetsuro Sasada, Kenichi Kohashi, Hideaki Bando, Itaru Endo, Tetsuya Nakatsura. Immunologic efficacy of heat shock protein 105 peptide vaccine in patients with advanced colorectal and esophageal cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A017.