abbreviatioNs CTL = cytotoxic T lymphocyte; DC = dendritic cell; HLA = human leukocyte antigen; IL = interleukin; Ke = kiloequivalent; KPS = Karnofsky Performance Scale; MST = median overall survival time; PD = progressive disease; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; TAA = tumor-associated antigen; WT1 = Wilms' tumor 1. Department of Neurosurgery, National Hospital Organization, Shinshu Ueda Medical Center, Ueda, Nagano, Japan obJect Dendritic cell (DC)-based vaccination is considered a potentially effective therapy against advanced cancer. The authors conducted a Phase I study to investigate the safety and immunomonitoring of Wilms' tumor 1 (WT1)-pulsed DC vaccination therapy for patients with relapsed malignant glioma. methods WT1-pulsed and/or autologous tumor lysate-pulsed DC vaccination therapy was performed in patients with relapsed malignant gliomas. Approximately 1 × 10 7 to 2 × 10 7 pulsed DCs loaded with WT1 peptide antigen and/or tumor lysate were intradermally injected into the axillary areas with OK-432, a streptococcal preparation, at 2-week intervals for at least 5-7 sessions (1 course) during an individual chemotherapy regimen. results Ten patients (3 men, 7 women; age range 24-64 years [median 39 years]) with the following tumors were enrolled: glioblastoma (6), anaplastic astrocytoma (2), anaplastic oligoastrocytoma (1), and anaplastic oligodendroglioma (1). Modified WT1 peptide-pulsed DC vaccine was administered to 7 patients, tumor lysate-pulsed DC vaccine to 2 patients, and both tumor lysate-pulsed and WT1-pulsed DC vaccine to 1 patient. The clinical response was stable disease in 5 patients with WT1-pulsed DC vaccination. In 2 of 5 patients with stable disease, neurological findings improved, and MR images showed tumor shrinkage. No serious adverse events occurred except Grade 1-2 erythema at the injection sites. WT1 tetramer analysis detected WT1-reactive cytotoxic T cells after vaccination in patients treated with WT1-pulsed therapy. Positivity for skin reaction at the injection sites was 80% (8 of 10 patients) after the first session, and positivity remained for these 8 patients after the final session. coNclusioNs This study of WT1-pulsed DC vaccination therapy demonstrated safety, immunogenicity, and feasibility in the management of relapsed malignant gliomas.

Despite significant recent advances in the development of immune checkpoint inhibitors, the treatment of advanced colorectal cancer involving metastasis to distant organs remains challenging. We conducted a phase I study to investigate the safety and immunogenicity of Wilms’ tumor (WT1) class I/II peptides-pulsed dendritic cell DC vaccination for patients with advanced colorectal cancer. Standard treatment comprising surgical resection and chemotherapy was followed by one course of seven biweekly administrations of 1–2 × 107 DCs with 1–2 KE of OK-432 (streptococcal preparation) in three patients. Clinical efficacy was confirmed based on WT1 expression using immunohistochemistry on paraffin-embedded tissues and immune monitoring using tetramer analysis and enzyme-linked immunosorbent spot (ELISPOT) assays. WT1 expression with human leukocyte antigen (HLA)-class I molecules was detected in surgical resected tissues. Adverse reactions to DC vaccinations were tolerable under an adjuvant setting. WT1-specific cytotoxic T cells were detected by both modified WT1-peptide/HLA-A*24:02 tetramer analysis and/or interferon-γ-producing cells through the use of ELISPOT assays after the first DC vaccination. Immunity acquired from DC vaccination persisted for two years with prolonged disease-free and overall survival. The present study indicated that DC vaccination targeting WT1 demonstrated the safety and immunogenicity as an adjuvant therapy in patients with resectable advanced colorectal cancer.

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Active human dendritic cells (DCs), which efficiently induce immune responses through their functions as antigen-presenting cells, exhibit direct anti-tumour killing activity in response to some pathogens and cytokines. These antigen-presenting and tumour killing abilities may provide a breakthrough in cancer immunotherapy. However, the mechanisms underlying this killer DC activity have not been fully proven, despite the establishment of interferon-α (IFN-α)-generated killer DCs (IFN-DCs). Here mature IFN-DCs (mIFN-DCs), generated from IFN-DCs primed with OK-432 (streptococcal preparation), exhibited elevated expression of CD86 and human leukocyte antigen-DR (minimum criteria for DC vaccine clinical trials) as well as antigen-presenting abilities comparable with those of mature IL-4-DCs (mIL-4-DCs). Interestingly, the killing activity of mIFN-DCs, which correlated with the expression of CD56 (natural killer cell marker) and was activated via the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand pathway, was stronger than that of IFN-DCs and remarkably stronger than that of mIL-4-DCs. Therefore, mIFN-DCs exhibit great potential as an anti-cancer vaccine that would promote both acquired immunity and direct tumour killing.

Abstract. Background/Aim: Wilms' tumor 1 (WT1) is a tumor-associated antigen highly expressed in cancer. We examined the safety of WT1-peptide pulsed dendritic cell (WT1-DC) vaccine in combination withAlthough several treatment approaches, such as surgery and chemotherapy, have been used for treating pancreatic cancer, its prognosis remains poor, and further improvement in the treatment outcome is required (1-4). Recently, immunotherapy has been put forward as a new treatment approach for such cancer types with poor prognosis, and various methods have been examined in practice (1, 2, 5-7). In immunotherapy, selection of the tumor-associated antigen (TAA) is important. It has been reported that the Wilms' tumor 1 (WT1) antigen is highly expressed in various malignancies (8), including pancreatic cancer (8,9). Therefore, WT1 has been used as one of the targets of immunotherapy for pancreatic cancer (1, 7). For advanced pancreatic cancer, a WT1-peptide vaccine and WT1-peptide pulsed-dendritic cell (WT1-DC) vaccine have already been used in combination with chemotherapy agents, such as gemcitabine and S-1, in multiple studies, and its safety has been verified (10-16). Additionally, its clinical effects have been reported (11)(12)(13). Positive findings, such as WT1-specific delayed-type hypersensitivity after administration of the WT1-DC vaccine, reduced neutrophil/lymphocyte ratio in peripheral blood before or after administration, increased expression of CD83/human leukocyte antigen (HLA)-DR on DCs after administration, and no increase in interleukin-6 levels in peripheral blood after administration, have been reported as prognostic factors (13,15,16 (11,12).For patients diagnosed with primary pancreatic cancer, resection is the most important treatment, and implementation of postoperative chemotherapy can improve prognosis. In a recent report, the administration of S-1 alone was shown to be superior to that of gemcitabine for pancreatic cancer after resection (25). However, recurrence after surgery remains a serious problem. Therefore, the use of immunotherapy in combination with standard chemotherapy in the early phase can be considered as a strategy for the prevention of the recurrence of pancreatic cancer. Thus, in this study, we examined the safety of WT1-DC vaccine and acquisition of WT1-specific CTLs after administration of the vaccine with OK-432 as an adjuvant combined with chemotherapy (mainly S-1) in patients with surgically resected pancreatic cancer. Materials and MethodsPatient selection. Between August 2013 and March 2016, patients with pancreatic cancer were consecutively enrolled in this study. During this period, patients with several types of cancer received the WT1-DC vaccine at the Center for Advanced Cell Therapy in Shinshu University Hospital (26). We selected those with pancreatic cancer who underwent resection after initial diagnosis and then received chemotherapy. We excluded patients who received chemotherapy before surgery. Other eligibility criteria have been previously described (27)....