Search

Pediatric refractory solid tumors are aggressive malignant diseases, resulting in an extremely poor prognosis. KOC1, FOXM1, and KIF20A are cancer antigens that could be ideal targets for anticancer immunotherapy against pediatric refractory solid tumors with positive expression for these antigens. This nonrandomized, open‐label, phase I clinical trial evaluated the safety and efficacy of the NCCV Cocktail‐1 vaccine, which is a cocktail of cancer peptides derived from KOC1, FOXM1, and KIF20A, in patients with pediatric refractory solid tumors. Twelve patients with refractory pediatric solid tumors underwent NCCV Cocktail‐1 vaccination weekly by intradermal injections. The primary endpoint was the safety of the NCCV Cocktail‐1 vaccination, and the secondary endpoints were the immune response, as measured by interferon‐r enzyme‐linked immunospot assay, and the clinical outcomes including tumor response and progression‐free survival. The NCCV Cocktail‐1 vaccine was well tolerated. The clinical response of this trial showed that 4 patients had stable disease after 8 weeks and 2 patients maintained remission for >11 months. In 4, 8, and 5 patients, the NCCV Cocktail‐1 vaccine induced the sufficient number of peptide‐specific CTLs for KOC1, FOXM1, and KIF20A, respectively. Patients with high peptide‐specific CTL frequencies for KOC1, FOXM1, and KIF20A had better progression‐free survival than those with low frequencies. The findings of this clinical trial showed that the NCCV Cocktail‐1 vaccine could be a novel therapeutic strategy, with adequate effects against pediatric refractory solid tumors. Future large‐scale trials should evaluate the efficacy of the NCCV Cocktail‐1 vaccination., Kaplan‐Meier curves for progression‐free survival. We found that patients with higher numbers of cancer antigens (KOC1, FOXM1, and KIF20A) that induced peptide‐specific CTLs by vaccination had better progression‐free survival.

Heat shock protein 105 (HSP105) is overexpressed in many cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We carried out a phase I clinical trial of HLA‐A24‐ and HLA‐A2‐restricted HSP105 peptide vaccines in patients with CRC or EC. In this additional study of the trial, we examined the immunological efficacy of the novel vaccine. Thirty patients with advanced CRC or EC underwent HSP105 peptide vaccination. Immunological responses were evaluated by ex vivo and in vitro γ‐interferon enzyme‐linked immunospot assays and their correlation with patients’ prognosis was analyzed. The HSP105 peptide vaccines induced peptide‐specific CTLs in 15 of 30 patients. Among HLA‐A24 patients (n = 15), 7 showed induction of CTLs only ex vivo, whereas among HLA‐A2 patients (n = 15), 4 showed the induction ex vivo and 6 in vitro. Heat shock protein 105‐specific CTL induction correlated with suppression of cancer progression and was revealed as a potential predictive biomarker for progression‐free survival (P = .008; hazard ratio = 3.03; 95% confidence interval, 1.34‐6.85) and overall survival (P = .025; hazard ratio = 2.72; 95% confidence interval, 1.13‐6.52). Production of cytokines by HSP105 peptide‐specific CTLs was observed at the injection sites (skin) and tumor tissues, suggesting that HSP105‐specific CTLs not only accumulated at vaccination sites but also infiltrated tumors. Furthermore, we established 2 HSP105 peptide‐specific CTL clones, which showed HSP105‐specific cytokine secretion and cytotoxicity. Our results suggest that the HSP105 peptide vaccine could induce immunological effects in cancer patients and improve their prognosis.

The carcinoembryonic antigen glypican-3 (GPC3) is a good target of anticancer immunotherapy against pediatric solid tumors expressing GPC3. In this non-randomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3-peptide vaccination in patients with pediatric solid tumors. Eighteen patients with pediatric solid tumors expressing GPC3 underwent GPC3-peptide vaccination (intradermal injections every 2 weeks), with the primary endpoint being the safety of GPC3-peptide vaccination and the secondary endpoints being immune response, as measured by interferon (IFN)-γ enzyme-linked immunospot assay and Dextramer staining, and the clinical outcomes of tumor response, progression free survival (PFS), and overall survival (OS). Our findings indicated that GPC3 vaccination was well tolerated. We observed disease-control rates [complete response (CR)+partial response+stable disease] of 66.7% after 2 months, and although patients in the progression group unable to induce GPC3-peptide-specific cytotoxic T lymphocytes (CTLs) received poor prognoses, patients in the partial-remission and remission groups or those with hepatoblastoma received good prognoses. The GPC3-peptide vaccine induced a GPC3-specific CTL response in seven patients, with PFS and OS significantly longer in patients with high GPC3-specific CTL frequencies than in those with low frequencies. Furthermore, we established GPC3-peptide-specific CTL clones from a resected-recurrent tumor from one patient, with these cells exhibiting GPC3-peptide-specific cytokine secretion. The results of this trial demonstrated that the GPC3-peptide-specific CTLs induced by the GPC3-peptide vaccine infiltrated tumor tissue, and use of the GPC3-peptide vaccine might prevent the recurrence of pediatric solid tumors, especially hepatoblastomas, after a second CR.

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.