[Show abstract][Hide abstract] ABSTRACT: The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and only a few standard treatments are available for this condition. We performed a phase I trial to investigate the safety, immune response and anti-tumor effect of vaccination with three peptides derived from cancer-testis antigens.
This study was conducted as a phase I trial. Nine patients with advanced BTC who had unresectable tumors and were refractory to standard chemotherapy were enrolled. Three HLA-A*2402 restricted epitope peptides-cell division cycle associated 1 (CDCA1), cadherin 3 (CDH3) and kinesin family member 20A (KIF20A)-were administered subcutaneously, and the adverse events and immune response were assessed. The clinical effects observed were the tumor response, progression-free survival (PFS) and overall survival (OS).
The three-peptide vaccination was well-tolerated up to a dose of 3 mg per peptide (9 mg total). No grade 3 or 4 adverse events were observed after vaccination. Peptide-specific T cell immune responses were observed in all patients and stable disease was observed in 5 of 9 patients. The median PFS and OS were 3.4 and 9.7 months. The Grade 2 injection site reaction and continuous vaccination after PD judgment appeared to be prognostic of OS.
Multiple-peptide vaccination was well tolerated and induced peptide-specific T-cell responses.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR000003229).
Full-text · Article · Mar 2014 · Journal of Translational Medicine
[Show abstract][Hide abstract] ABSTRACT: The prognosis of patients with advanced pancreatic cancer is extremely poor and there are only a few standard treatments. Here, we report the results of a Phase I clinical trial to investigate the safety, immunostimulatory effects, and antineoplastic activity of a multi-target vaccine composed of four distinct peptides derived from cancer-testis (CT) antigens and vascular endothelial growth factor receptors (VEGFRs). Nine patients with unresectable, advanced pancreatic cancer who were refractory to standard chemotherapy were enrolled. Each patient was vaccinated with HLA-A*2402-restricted peptides derived from the CT antigens kinesin family member 20A (KIF20A) and cell division cycle-associated 1 (CDCA1) as well as from VEGFR1 and VEGFR2 subcutaneously once a week, and disease progression was evaluated up to 6 mo later. Adverse events were assessed using the Common Terminology Criteria for Adverse Events v. 3.0. Immunological responses were monitored by ELISPOT assays and flow cytometry based on peptide-specific dextramers. The clinical outcomes that were measured were tumor response, progression-free survival (PFS) and overall survival (OS). In general, the multi-peptide vaccine was well-tolerated, and no grade 3 or 4 adverse events were observed upon vaccination. Peptide-specific T-cell responses were detected in all 9 patients, and clinical benefits were observed in four of them. Median PFS and OS were 90 and 207 d, respectively. The elicitation of multiple and robust peptide-specific T-cell responses as well as the status of host lymphocytes may be useful prognostic factors among patients with advanced pancreatic cancer treated with peptide-based anticancer vaccines.
[Show abstract][Hide abstract] ABSTRACT: Background
Elucidation of the mechanisms by which gastric cancer cells acquire resistance to 5-fluorouracil (5FU) may provide important clues to the development of effective chemotherapy for 5FU-resistant gastric cancer
Four 5FU-resistant cell lines (MKN45/5FU, MKN74/5FU, NCI-N87/5FU, and KATOIII/5FU) were established by continuous exposure of the cells to progressively increasing concentrations of 5FU for about 1 year. Then, mRNA expression levels of four genes associated with 5FU metabolism, i.e., thymidylate synthase (TS), dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase, were quantitatively evaluated by real-time reverse transcriptase-polymerase chain reaction. In addition, TS protein expression was measured by Western blot analysis.
As compared with the parent cell lines, the 5FU-resistant cell lines showed 3.8- to 11.6-fold higher resistance to 5FU, as well as 1.9- to 3.5-fold higher TS mRNA expression and 1.6- to 7.1-fold higher TS protein expression. In contrast, the expressions of other genes did not differ significantly among the cell lines. The cytotoxicity of 5FU was enhanced 2.3- to 2.8 fold by leucovorin (LV) against three of the four 5FU-resistant cell lines.
Collectively, LV enhanced the cytotoxicity of 5FU not only against the parent gastric cancer cell lines, but also against the 5FU-resistant cell lines, even those with elevated TS expression levels. These results suggest that clinical studies of a combination of 5FU and LV are warranted in patients who have recurrent gastric cancer after 5FU-based therapy.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and there are only a few standard treatments. We conducted a phase I trial to investigate the safety, immune response, and antitumor effect of vaccination with four peptides derived from cancer-testis antigens, with a focus on their fluctuations during long-term vaccination until the disease had progressed.
Nine patients with advanced BTC who had unresectable tumors and were refractory to standard chemotherapy were enrolled. HLA-A*2402-restricted epitope peptides, lymphocyte antigen 6 complex locus K, TTK protein kinase, insulin-like growth factor-II mRNA-binding protein 3, and DEP domain containing 1 were vaccinated subcutaneously once a week at doses of 0.5, 1, or 2 mg and continued until disease progression. The adverse events were assessed by Common Terminology Criteria for Adverse Events and the immune response was monitored by an enzyme-linked immunospot assay or by flow cytometry. The clinical effects observed were tumor response, progression-free survival (PFS), and overall survival (OS).
Four-peptide vaccination was well tolerated. No grade 3 or 4 adverse events were observed. Peptide-specific T-cell immune responses were observed in seven of nine patients and clinical responses were observed in six of nine patients. The median PFS and OS were 156 and 380 days. The injection site reaction and CTL induction seemed to be prognostic factors of both PFS and OS.
Four-peptide vaccination was well tolerated and seemed to provide some clinical benefit to some patients. These immunologic and clinical responses were maintained over the long term through continuous vaccinations.
Full-text · Article · Mar 2013 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the safety and efficacy of combinatorial use of granulocyte-macrophage colony-stimulating factor (GM-CSF) and CpG oligodeoxynucleotides (CpG-ODN) as immunoenhancement adjuvants in Wilms' Tumor 1 (WT1) vaccine therapy for patients with solid malignancy.
The patients were placed into treatment groups as follows: WT1 peptide alone, WT1 peptide with GM-CSF (100 μg) and WT1 peptide with CpG-ODN (100 μg). HLA-A *2402 or *0201/*0206-restricted, WT1 peptide emulsified with Montanide ISA51 was injected intradermally every week for eight weeks. Toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 3.0. Tumor size, which was measured by computed tomography, was determined every four weeks. The responses were analyzed according to Response Evaluation Criteria in Solid Tumors.
The protocol was well tolerated; only local erythema occurred at the WT1 vaccine injection site. The disease control rate of the groups treated with WT1 peptide alone (n=10), with combinatorial use of GM-CSF (n=8) and with combinatorial use of CpG-ODN (n=10), in the initial two months was 20%, 25% and 60%, respectively.
Addition of GM-CSF or CpG-ODN to the WT1 peptide vaccine for patients with solid malignancy was safe and improved the effectiveness of clinical response.
Full-text · Article · Jun 2012 · Anticancer research
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress in cancer patients has been demonstrated to be partly mediated by neutrophils. Although it is reported that natural antioxidants, such as green tea extract, reduce oxidative stress, there is limited evidence of their effects in cancer patients. This study aimed to determine the effect of green tea extract on reactive oxygen species produced by neutrophils from cancer patients.
Peripheral blood samples were obtained from eighteen patients with advanced cancer. Green tea extract was added to the blood samples with luminol on Mebiol gel, and luminol-dependent chemiluminescence was measured to monitor the production of reactive oxygen species from migrated neutrophils into the gel, at 37°C.
Luminol-dependent chemiluminescence was significantly down-regulated in the presence of green tea extract in a concentration-dependent manner.
These results indicate the antioxidant effect of green tea extract on reactive oxygen species produced by neutrophils, which may be effective in reducing oxidative stress in cancer patients.
Full-text · Article · Jun 2012 · Anticancer research
[Show abstract][Hide abstract] ABSTRACT: Although the systemic inflammatory condition can be confirmed in cancer patients, the pathophysiological importance of reactive oxygen species (ROS) produced by neutrophils has not yet been defined.
Twenty-one patients with inoperable, chemoresistant and radioresistant cancer were enrolled in this study. At least 4 weeks prior to sampling, the patients were free from antitumor treatments. Control samples were also obtained from a healthy donor (39-year-old male). Peripheral blood samples were set 150 μl each on the 2 ml tube with 50 μl Mebiol Gel, and the production of ROS from neutrophils was detected by luminol-dependent chemiluminescence (LmCL) in a kinetic mode at 30-minute intervals for 2.5 hours with a luminometer at 37°C.
Each point, peak value and sum of values of LmCL in the patient group was statistically higher than those in the healthy donor. There were no differences in LmCL according to performance status (PS), type of cancer, age, or gender in cancer patients.
Our findings suggested that ROS produced by neutrophils universally reflects the systemic inflammatory condition in cancer patients.
Full-text · Article · Feb 2012 · Anticancer research
[Show abstract][Hide abstract] ABSTRACT: Gene expression analyses may play useful roles in determining the prognosis of cancer patients and in selecting antitumor drugs. This retrospective study examined potential prognostic factors in patients with pancreatic cancer who received adjuvant chemotherapy after surgery. The study group consisted of 79 patients who had received gemcitabine or S-1 as adjuvant chemotherapy for advanced pancreatic cancer. Using laser-captured microdissection and real-time RT-PCR assay, we quantitatively evaluated the mRNA levels of 10 genes associated with patient prognosis and sensitivity to chemotherapy using paraffin-embedded specimens of the primary tumors resected before the start of adjuvant chemotherapy. In univariate analyses, a low gene expression level of γ-glutamyl hydrolase (GGH) and a high gene expression level of folylpolyglutamate synthase correlated with a favorable outcome. In a multivariate analysis, a low gene expression level of dihydropyrimidine dehydrogenase (DPD) and GGH significantly correlated with outcome (hazard ratio of the high DPD group to the low DPD group: 5.55; 95% confidence interval (CI) 1.27-24.05; P=0.022; the high GGH group to the low GGH group: 3.77; 95% CI 1.04-13.79, P=0.043). For adjuvant chemotherapy of patients with pancreatic cancer, the mRNA level of DPD and GGH may affect the prognosis of these patients.
Preview · Article · Nov 2011 · Experimental and therapeutic medicine
[Show abstract][Hide abstract] ABSTRACT: Recently, analysis of tumor antigen using the microarray method revealed up-regulation of cancer-testis antigens, RNF43, and TOMM34, and vascular endothelial growth factor receptors, VEGFR1 and VEGFR2, in colorectal cancer. Using the synthesized peptide of those tumor antigens, we performed a phase I clinical trial of peptide vaccine therapy together with anticancer drugs for advanced colorectal cancer to confirm the safety of the treatment. The subjects were patients with inoperable colorectal cancer or progressive disease after standard chemotherapy. The HLA type of the patients was HLA-A2402. The primary endpoint of the trial was observation of the adverse events determined by NCI-CTCAE criteria, and the secondary endpoints were the size of the tumor and the amount of CTL in the peripheral blood of patients after treatment. We performed vaccine therapy 128 times for the 10 patients from July 2008 to July 2009. The adverse events were grade 1 redness and induration, grade 2 skin ulcer at the vaccine site and grade 1 pyrexia. All patients tolerated the treatment. The evaluation of the tumor imaging revealed 1 PR, 7 SD and 2 PD after 1 course of treatment. We demonstrated a CTL assay in 5 patients (1 PR, 3 SD and 1 PD), and therefore we observed an increase in the peptide-specific CTL in the PR and SD patients.
[Show abstract][Hide abstract] ABSTRACT: In a body that is host to a tumor, the body's natural defenses work to eliminate the tumor. However, the immune response is weak compared to the proliferative capacity of cancer cells and the body's defenses are inadequate. The volume of a tumor in the body is recognized to be the difference between the action of the body's defense to eliminate the tumor and the proliferative capacity of the tumor itself. Current treatments, however, are directed mainly against the proliferating tumor cells, with almost nothing done to boost the body's defense as it tries to eliminate the tumor. We have recently incorporated immune cell therapies (activated T cells and dendritic cell vaccine) as well as hyperthermia therapy in the fever range to strengthen the body's inadequate defense response. This has resulted in enhanced reduction of tumor volume, and is promising in terms of a strengthened quantitative effect. When the safety of this treatment is established and it is incorporated as an ancillary to standard treatment, we may expect augmentation of the quantitative effect in reducing tumor volume in cancer treatment. In recent years, however, the goal of cancer treatment is not only to reduce the tumor volume but also to have a qualitative effect on the patient, including quality of life (QOL). QOL is strongly affected by the patient's psychological condition, and falling into a depressive state decreases the strength of the body's natural defenses. In the development of cancer treatment with expectations for both a quantitative and qualitative response, we think that immunotherapy with a psychological approach will be important in future clinical settings.
[Show abstract][Hide abstract] ABSTRACT: A 53-year-old woman presented with a diagnosis of advanced gallbladder cancer at our hospital. She was evaluated with CT scan and given a diagnosis of Stage IVb due to the multiple lymph nodes metastases and significant invasion to the artery. However, we underwent simple cholecystectomy followed by immunotherapy that was the hope of herself and her family. The serum level of DUPAN-2 was gradually elevated to 6,800 U/mL, and the metastases to the liver were detected. After we started the dendritic cell vaccine pulsed with autologous tumor-lysate with S-1, DUPAN-2 decreased to 980 U/ mL. The CT scan showed complete response (CR) in the liver metastases and partial response (PR) in the lymph node metastases. However, the serum level of CEA elevated since the MUC-1 peptide was used instead of autologous tumor- lysate, even DUPAN-2 did not. The liver metastases were in control, but the lymph nodes metastases had progressed. She died of the progressed lesion later in approximately one year from the operation. This case demonstrated a possibility of the tumor escape mechanism by changing their tumor-associated antigens.
No preview · Article · Nov 2009 · Gan to kagaku ryoho. Cancer & chemotherapy
[Show abstract][Hide abstract] ABSTRACT: In public-sector cancer therapy, strict guidelines hold for each malignancy without considering the desire of patients. In contrast, cancer management in private institutions usually consists of treatment modalities, including biotherapy, to satisfy patient requirements and yet be feasible enough to perform on an outpatient basis. In our institute, we have employed immunotherapy utilizing CD3-activated T lymphocytes and dendritic cells, aiming to restore cancer immunotolerance. Furthermore, we have started combination immunotherapy with regional hyperthermia since 2007 with the purpose of making cancer cells more heterogenic. Based on clinical experience, the goal of cancer treatment is not only the direct local response of tumor, but improvement of overall health and the QOL of cancer patients in particular. Therefore, recently we have also focused on natural healing as part of our new integrated approach. This approach in our institute includes patient consultation regarding balanced nutrition and proper choice of medical supplements, together with stress management, aiming at improvement of patients' well-being. Accumulation of clinical data for their usefulness in this integrated approach is considered helpful in terms of development of new types of clinical trials in the future. Therefore, private medical institutes may serve not only for the treatment but for clinical research purposes as well.
[Show abstract][Hide abstract] ABSTRACT: Intrahepatic cholangiocellular carcinoma is one of the extremely high-grade malignancies in human gastrointestinal cancers. Even if the curative resection of the tumor could be performed, the recurrence and/or metastasis occurs frequently, and the prognosis after operation is very poor. There is no effective chemotherapy or radiation therapy after operation yet, so we performed a Phase II clinical study of adoptive transfer of T cells and vaccine (ATVAC) for ICC patients who received a curative resection of their tumors. From the results of the intermediate analysis, ATVAC could improve the postoperative recurrence-free survival and overall survival compared with that of the patients who received the surgery alone. Our Phase II study has already been completed, and we now plan to perform a Phase III prospective randomized trial. ICC is a rare tumor in Japan, and a joint study with several institutes should be designed to obtain enough candidates for the trial. We should first settle several problems such as the difficulty in producing the same quality of DCs and T cells in a GMP-grade CPC or securing sufficient funding in order to carry out the Phase III study.