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Mo1559 Phase I Clinical Trial of Peptide Vaccination With Urlc10 and VEGFR1 Epitope Peptides in Patients With Advanced Gastric Cancer
There is usefulness of gastrectomy for oral-intake function and the prognosis of single NF cases with chemotherapy after gastrectomy was especially favorable. Our study also revealed that the cases with multiple NFs still had poor prognosis but some cases receiving debulking surgery and chemotherapy had a relatively long survival as those with single NF.
AGA Abstracts
Mo1559 Phase I Clinical Trial of Peptide Vaccination With Urlc10 and VEGFR1 Epitope Peptides in Patients With Advanced Gastric Cancer Yoshie Higashihara, Junko Kato, Nobuko Serizawa, Tomohiro Kodani, Masae Konishi, Taro Osada, Takashi Yoshizawa, Akihito Nagahara, Sumio Watanabe Background and aims: Peptide vaccine treatment has attracted attention in recent years as a new therapy option for chemotherapy resistant, advanced, unresectable cancer. We conducted a phase I clinical trial for gastric cancer treatment with a peptide vaccine using an URLC10 origin HLA-A*2402-restrictive epitope peptide and a new blood vessel antigen epitope peptide of VEGFR1. From comprehensive genomic studies, these epitopes were determined to be tumor antigens. Methods: This study was a prospective non-randomized, single arm, phase I clinical trial with advanced gastric cancer that became chemotherapy resistant, since August 2009 in our hospital. We subcutaneously injected 2 mg/body each of HLA-A*2402 restrictive epitope peptide and incomplete Freund's adjuvant (IFA), which were identified as URLC10 and VEGFR1, in the inguinal region or an axillary region of the patients. URLC10 and VEGFR1 peptide were subcutaneously administered on days 1,8,15 and 22 in a-28-day treatment cycle. Safety was evaluated for each course 2 weeks after the end. One or more courses of therapy were defined as complete therapy. The curative outcome was analyzed approximately 29 days from the start of treatment. The administration of peptide vaccination was continued as long as possible until disease progression. The primary endpoint was safety and toxicity of the peptide vaccine treatment, and the secondary endpoint was immunological responses and clinical outcome. This study was approved by Hospital Ethics Committee. Results: A total of 14 patients were enrolled in this study. Twelve of 14 patients received four or more vaccinations (as least one course).There were 9 males and 3 females with the average age of 59.4 years. ECOG PS was 0 in 7 patients, 1 in 3 patients, and 2 in 2 patients. Two patients could not continued medication for progression of primary disease, which were not considered an adverse event with the peptide vaccine. Although skin reactions at the sites such as induration, rash and pruritus of Grade 2 were shown , there were no other adverse events, and we did not observe dose-limiting toxicity (DLT). The therapeutic effect after 1 course was 4 patients of stable disease (SD) and 8 patients of progressive disease (PD). Conclusions: The peptide vaccination with URLC10 and VEGFR1 epitope peptides in patients of advanced gastric cancer did not cause severe adverse events, and could be considered safe. Therefore, we consider that it will be feasible treatment for the patients with advanced gastric cancer that became chemotherapy resistant after the Phase II and phase III clinical trials.
Mo1557 DNA Methylation in Gastric Mucosae is Associated With the Severity of Mucosal Inflammation Involving the Risk of Diffuse-Type Gastric Cancer Takeichi Yoshida, Jun Kato, Takao Maekita, Satoshi Yamashita, Shotaro Enomoto, Toshikazu Ushijima, Masao Ichinose Background and aims: Aberrant DNA methylation observed in the atrophic gastritis with the past infection of Helicobacter pylori (H. pylori) is associated with the risk of gastric cancer, mainly intestinal-type. In contrast, DNA methylation in gastric mucosae at risk of diffusetype gastric cancer is not fully known. We have found that the subjects with severe gastric mucosal inflammation identified by serum markers have higher risk of the development of diffuse-type gastric cancer. Those who showed H. pylori antibody titer >500 U/mL, pepsinogen (PG) II >30 ng/mL, or PG I >70 ng/mL and PG I/II ratio <3.0 are all at high risk of diffusetype gastric cancer. The present study investigated whether aberrant DNA methylation is induced in gastric mucosae with active inflammation at high risk of diffuse-type cancer. Methods: Gastric mucosa DNA samples were collected from 78 healthy volunteers. Inflammatory status of gastric mucosa was evaluated by an H. pylori antibody titer or serum PGs. The methylation levels were measured at the promoter CpG islands of the six genes (hrasls, hand1, lox, thbd, flnc, and p41arc) by real-time methylation specific PCR, and at non-coding repetitive elements (Alu and Satα) by bisulfate pyrosequencing, of which methylation levels were reportedly altered in H. pylori-infected gastric mucosae. Results: The methylation levels at the promoter CpG islands were consistently increased in a stepwise manner with the increase of the serum levels of H. pylori antibody titer or PG II. In contrast, the methylation levels at repetitive elements were consistently decreased in a stepwise manner with the increase of serum levels of H. pylori antibody titer or PG II. Stratified by H. pylori antibody titer and PG II, the methylation levels were altered to the highest degree in the group with high titers of H. pylori antibody (>500 U/mL) and high levels of PG II (>30 ng/mL). The methylation levels were also severely altered in the subjects with serum PG I >70 ng/mL and PG I/II ratio <3.0. Conclusions: DNA methylation in gastric mucosae was closely associated with the severity of inflammation identified by serum H. pylori antibody or PGs. These results suggest that DNA methylation works to some extent in the occurrence of diffusetype gastric cancer resulting from severe active inflammation induced by H. pylori infection.
Mo1560 Impaired Autophagy in Gastric Carcinoids and Adenocarcinoma of Both Rodent Models and Patients Reidar Alexander Vigen, Yosuke Kodama, Trond Viset, Reidar Fossmark, Helge Waldum, Mark Kidd, Timothy C. Wang, Irvin Modlin, Duan Chen, Chun-Mei Zhao Background/Aim: Autophagy has been recently suggested as a target for anticancer therapy. However, the dual role of autophagy during gastric tumorigenesis, i.e. either having tumorpromoting or tumor-suppressing properties, is still unclear. In order to improve our understanding of autophagy in human gastric carcinoids and adenocarcinoma, in this study we employed immunohistochemistry to measure autophagy in rodent models as well as clinical samples. Methods: Gastric carcinoids in Mastomys were induced by giving loxtidine in drinking water for 27 weeks. Spontaneously developed gastric adenocarcinoma in the Japanese cotton rats and the so-called INS-GAS transgenic mice were collected. Tissue samples of gastric carcinoids or adenocarcinoma were collected from patients. Immunohistochemistry was performed against autophagy-related gene protein-6 (ATG6, also called beclin1), ATG-5 and ATG-16. Results: General histological appearances were similar with respect to carcinoids between the Mastomys and patients, and with respect to adenocarcinoma between the cotton rats, INS-GAS mice and patients. In tumor-free Mastomys, ATG-5, ATG16 and beclin-1 were immune-positive in the gastric mucosa. In tumor-bearing Mastomys, ATG-5 and ATG-16 were totally negative, whereas beclin-1 was positive in four of five animals. In ten patients with carcinoids, ATG-5 was negative in six of ten, ATG-16 negative in nine of ten patients, and beclin-1 negative in three of ten patients. In cotton rats, ATG5 and ATG-16 were negative in the tumor area and its adjacent tissue but positive in the normal area of the same stomachs. Beclin-1 was negative in three of five, and positive in small area of tumor in two of five cotton rats. In INS-GAS mice, ATG-5 and beclin-1 were positive in the tumor area, but the numbers of immunoreactive cells per gland were reduced by about 50% (p<0.01, n=10) in comparison with wild-type mice. ATG-16 antibody failed to work. In ten patients with adenocarcinoma, ATG-5 and ATG-16 were negative in eight of ten patients, and beclin-1 positive in all ten patients. Conclusions: We suggest that an impaired autophagy took place at the stage of formation of ATG-5-ATG-12-ATG-16 complex in both gastric carcinoids and adenocarcinoma of both rodent models and patients, and that ATG-5 and ATG-16 are better markers than beclin-1 in assessing the autophagy in these lesions. Stimulation of ATG-5-ATG-12-ATG-16 complex formation might be a novel target strategy for gastric anticancer therapy.
Mo1558 Evaluation of Treatment for Curatively Unresectable Gastric Cancer Tatsuto Nishigori, Yoshito Asao, Masato Kondo, Tsunehiro Yoshimura Background: Outcomes in patients with curatively unresectable gastric cancer were previously very poor, but have improved with the advent of new anticancer agents, including S-1 in Japan, enhancing the value of surgical therapy. A prospective randomized controlled designed to investigate the role of gastrectomy as well as chemotherapy in gastric cancer patients with single non-curative factor (NF) are ongoing. However it takes several years until the result comes out and the prognosis of patients with multiple NFs is not clear. Purpose: The purpose of our study was to evaluate results of recent treatments for gastric cancers with distant metastases and to identify factors that might influence these results. Patients and Methods: The study group comprised 209 patients with non-curatively resected gastric cancer who were treated at our hospital from January 2005 through December 2010. Result: The median survival time (MST) was 291 days, the one-year survival rate was 42.3% and three-year survival time was 16.1%. By the univariate analysis, significantly better outcomes were observed in patients with a history of chemotherapy and gastrectomy, no peritoneal dissemination and single NF than with no history of them, peritoneal dissemination and multiple NF. Firstly, based on the number of NF, we analysed 107 cases with single NF. The MSTs were 115 days in treatment free (F, n=9) group, 66 days in gastrojejunostomy(GJ, n=3) group, and 160 days in gastrectomy(G, n=2) group. On the other hand, The MSTs of patients with chemotherapy were relatively long, such as 325 days in chemotherapy(C, n=42) group, 439 days in GJ and C(n=13) group, and 871days in G and C(n=38) group. Secondly, we analysed 102 cases with multiple NFs. The MSTs were 50 days in F(n=22) group, 52 days in GJ(n=4) group, 119 days in G(n=3) group, 256 days in C(n=51) group, 284 days in GJ and C(n=12) group, and 755 days in G and C(n=10) group. Finally, we analyzed the median food-intake periods for each groups, which were 57days in F group, 287 days in C group, 284 days in GJ group, and 755 days in G group. The percentage of cases which oral-intake period was more than 90% of survival time accounted for 19, 56, 50, 77% in each groups. Conclusion: Our study suggests that the survival time was significant prolong in cases with chemotherapy including S-1 compared with those with surgery alone and no treatment.
AGA Abstracts
S-628
AGA Abstracts
Mo1559 Phase I Clinical Trial of Peptide Vaccination With Urlc10 and VEGFR1 Epitope Peptides in Patients With Advanced Gastric Cancer Yoshie Higashihara, Junko Kato, Nobuko Serizawa, Tomohiro Kodani, Masae Konishi, Taro Osada, Takashi Yoshizawa, Akihito Nagahara, Sumio Watanabe Background and aims: Peptide vaccine treatment has attracted attention in recent years as a new therapy option for chemotherapy resistant, advanced, unresectable cancer. We conducted a phase I clinical trial for gastric cancer treatment with a peptide vaccine using an URLC10 origin HLA-A*2402-restrictive epitope peptide and a new blood vessel antigen epitope peptide of VEGFR1. From comprehensive genomic studies, these epitopes were determined to be tumor antigens. Methods: This study was a prospective non-randomized, single arm, phase I clinical trial with advanced gastric cancer that became chemotherapy resistant, since August 2009 in our hospital. We subcutaneously injected 2 mg/body each of HLA-A*2402 restrictive epitope peptide and incomplete Freund's adjuvant (IFA), which were identified as URLC10 and VEGFR1, in the inguinal region or an axillary region of the patients. URLC10 and VEGFR1 peptide were subcutaneously administered on days 1,8,15 and 22 in a-28-day treatment cycle. Safety was evaluated for each course 2 weeks after the end. One or more courses of therapy were defined as complete therapy. The curative outcome was analyzed approximately 29 days from the start of treatment. The administration of peptide vaccination was continued as long as possible until disease progression. The primary endpoint was safety and toxicity of the peptide vaccine treatment, and the secondary endpoint was immunological responses and clinical outcome. This study was approved by Hospital Ethics Committee. Results: A total of 14 patients were enrolled in this study. Twelve of 14 patients received four or more vaccinations (as least one course).There were 9 males and 3 females with the average age of 59.4 years. ECOG PS was 0 in 7 patients, 1 in 3 patients, and 2 in 2 patients. Two patients could not continued medication for progression of primary disease, which were not considered an adverse event with the peptide vaccine. Although skin reactions at the sites such as induration, rash and pruritus of Grade 2 were shown , there were no other adverse events, and we did not observe dose-limiting toxicity (DLT). The therapeutic effect after 1 course was 4 patients of stable disease (SD) and 8 patients of progressive disease (PD). Conclusions: The peptide vaccination with URLC10 and VEGFR1 epitope peptides in patients of advanced gastric cancer did not cause severe adverse events, and could be considered safe. Therefore, we consider that it will be feasible treatment for the patients with advanced gastric cancer that became chemotherapy resistant after the Phase II and phase III clinical trials.
Mo1557 DNA Methylation in Gastric Mucosae is Associated With the Severity of Mucosal Inflammation Involving the Risk of Diffuse-Type Gastric Cancer Takeichi Yoshida, Jun Kato, Takao Maekita, Satoshi Yamashita, Shotaro Enomoto, Toshikazu Ushijima, Masao Ichinose Background and aims: Aberrant DNA methylation observed in the atrophic gastritis with the past infection of Helicobacter pylori (H. pylori) is associated with the risk of gastric cancer, mainly intestinal-type. In contrast, DNA methylation in gastric mucosae at risk of diffusetype gastric cancer is not fully known. We have found that the subjects with severe gastric mucosal inflammation identified by serum markers have higher risk of the development of diffuse-type gastric cancer. Those who showed H. pylori antibody titer >500 U/mL, pepsinogen (PG) II >30 ng/mL, or PG I >70 ng/mL and PG I/II ratio <3.0 are all at high risk of diffusetype gastric cancer. The present study investigated whether aberrant DNA methylation is induced in gastric mucosae with active inflammation at high risk of diffuse-type cancer. Methods: Gastric mucosa DNA samples were collected from 78 healthy volunteers. Inflammatory status of gastric mucosa was evaluated by an H. pylori antibody titer or serum PGs. The methylation levels were measured at the promoter CpG islands of the six genes (hrasls, hand1, lox, thbd, flnc, and p41arc) by real-time methylation specific PCR, and at non-coding repetitive elements (Alu and Satα) by bisulfate pyrosequencing, of which methylation levels were reportedly altered in H. pylori-infected gastric mucosae. Results: The methylation levels at the promoter CpG islands were consistently increased in a stepwise manner with the increase of the serum levels of H. pylori antibody titer or PG II. In contrast, the methylation levels at repetitive elements were consistently decreased in a stepwise manner with the increase of serum levels of H. pylori antibody titer or PG II. Stratified by H. pylori antibody titer and PG II, the methylation levels were altered to the highest degree in the group with high titers of H. pylori antibody (>500 U/mL) and high levels of PG II (>30 ng/mL). The methylation levels were also severely altered in the subjects with serum PG I >70 ng/mL and PG I/II ratio <3.0. Conclusions: DNA methylation in gastric mucosae was closely associated with the severity of inflammation identified by serum H. pylori antibody or PGs. These results suggest that DNA methylation works to some extent in the occurrence of diffusetype gastric cancer resulting from severe active inflammation induced by H. pylori infection.
Mo1560 Impaired Autophagy in Gastric Carcinoids and Adenocarcinoma of Both Rodent Models and Patients Reidar Alexander Vigen, Yosuke Kodama, Trond Viset, Reidar Fossmark, Helge Waldum, Mark Kidd, Timothy C. Wang, Irvin Modlin, Duan Chen, Chun-Mei Zhao Background/Aim: Autophagy has been recently suggested as a target for anticancer therapy. However, the dual role of autophagy during gastric tumorigenesis, i.e. either having tumorpromoting or tumor-suppressing properties, is still unclear. In order to improve our understanding of autophagy in human gastric carcinoids and adenocarcinoma, in this study we employed immunohistochemistry to measure autophagy in rodent models as well as clinical samples. Methods: Gastric carcinoids in Mastomys were induced by giving loxtidine in drinking water for 27 weeks. Spontaneously developed gastric adenocarcinoma in the Japanese cotton rats and the so-called INS-GAS transgenic mice were collected. Tissue samples of gastric carcinoids or adenocarcinoma were collected from patients. Immunohistochemistry was performed against autophagy-related gene protein-6 (ATG6, also called beclin1), ATG-5 and ATG-16. Results: General histological appearances were similar with respect to carcinoids between the Mastomys and patients, and with respect to adenocarcinoma between the cotton rats, INS-GAS mice and patients. In tumor-free Mastomys, ATG-5, ATG16 and beclin-1 were immune-positive in the gastric mucosa. In tumor-bearing Mastomys, ATG-5 and ATG-16 were totally negative, whereas beclin-1 was positive in four of five animals. In ten patients with carcinoids, ATG-5 was negative in six of ten, ATG-16 negative in nine of ten patients, and beclin-1 negative in three of ten patients. In cotton rats, ATG5 and ATG-16 were negative in the tumor area and its adjacent tissue but positive in the normal area of the same stomachs. Beclin-1 was negative in three of five, and positive in small area of tumor in two of five cotton rats. In INS-GAS mice, ATG-5 and beclin-1 were positive in the tumor area, but the numbers of immunoreactive cells per gland were reduced by about 50% (p<0.01, n=10) in comparison with wild-type mice. ATG-16 antibody failed to work. In ten patients with adenocarcinoma, ATG-5 and ATG-16 were negative in eight of ten patients, and beclin-1 positive in all ten patients. Conclusions: We suggest that an impaired autophagy took place at the stage of formation of ATG-5-ATG-12-ATG-16 complex in both gastric carcinoids and adenocarcinoma of both rodent models and patients, and that ATG-5 and ATG-16 are better markers than beclin-1 in assessing the autophagy in these lesions. Stimulation of ATG-5-ATG-12-ATG-16 complex formation might be a novel target strategy for gastric anticancer therapy.
Mo1558 Evaluation of Treatment for Curatively Unresectable Gastric Cancer Tatsuto Nishigori, Yoshito Asao, Masato Kondo, Tsunehiro Yoshimura Background: Outcomes in patients with curatively unresectable gastric cancer were previously very poor, but have improved with the advent of new anticancer agents, including S-1 in Japan, enhancing the value of surgical therapy. A prospective randomized controlled designed to investigate the role of gastrectomy as well as chemotherapy in gastric cancer patients with single non-curative factor (NF) are ongoing. However it takes several years until the result comes out and the prognosis of patients with multiple NFs is not clear. Purpose: The purpose of our study was to evaluate results of recent treatments for gastric cancers with distant metastases and to identify factors that might influence these results. Patients and Methods: The study group comprised 209 patients with non-curatively resected gastric cancer who were treated at our hospital from January 2005 through December 2010. Result: The median survival time (MST) was 291 days, the one-year survival rate was 42.3% and three-year survival time was 16.1%. By the univariate analysis, significantly better outcomes were observed in patients with a history of chemotherapy and gastrectomy, no peritoneal dissemination and single NF than with no history of them, peritoneal dissemination and multiple NF. Firstly, based on the number of NF, we analysed 107 cases with single NF. The MSTs were 115 days in treatment free (F, n=9) group, 66 days in gastrojejunostomy(GJ, n=3) group, and 160 days in gastrectomy(G, n=2) group. On the other hand, The MSTs of patients with chemotherapy were relatively long, such as 325 days in chemotherapy(C, n=42) group, 439 days in GJ and C(n=13) group, and 871days in G and C(n=38) group. Secondly, we analysed 102 cases with multiple NFs. The MSTs were 50 days in F(n=22) group, 52 days in GJ(n=4) group, 119 days in G(n=3) group, 256 days in C(n=51) group, 284 days in GJ and C(n=12) group, and 755 days in G and C(n=10) group. Finally, we analyzed the median food-intake periods for each groups, which were 57days in F group, 287 days in C group, 284 days in GJ group, and 755 days in G group. The percentage of cases which oral-intake period was more than 90% of survival time accounted for 19, 56, 50, 77% in each groups. Conclusion: Our study suggests that the survival time was significant prolong in cases with chemotherapy including S-1 compared with those with surgery alone and no treatment.
AGA Abstracts
S-628