title: Locoregional immunotherapy of malignant ascites from gastric cancer using DTH-oriented doses of the streptococcal preparation OK-432: Treatment of Th1 dysfunction in the ascites microenvironment.
abstract: Locoregional administration of the streptococcal preparation OK-432 is effective in treating malignant ascites from gastric cancer. In order to enhance the efficacy, we conducted a pilot study of locoregional immunotherapy for malignant ascites using host-oriented doses of OK-432. Moreover, action mechanisms of OK-432 were further explored in view of the T-helper type 1 (Th1)-Th2 concept. Gastric cancer patients with cytologically determined malignant ascites were locoregionally administered with OK-432. The dose of OK-432 was selected according to the delayed-type hypersensitivity (DTH) reaction levels to OK-432. Cytokine production profiles of ascites cells were determined using whole ascites assay by stimulation with OK-432. IL-10 mRNA expression was analyzed using RT-PCR. It was found that a positive clinical response was observed in 37 of the 51 (73%) patients with the DTH-oriented approach, showing a significantly higher efficacy than traditional dosage methods using empirical doses (31/58, 53%) (p=0.0487). The DTH-oriented administration of OK-432 produced adverse effects such as fever elevation (p<0.0001) and abdominal pain (p=0.0013) to a significantly lesser extent compared with the traditional treatment. Analysis of the action mechanism of OK-432 revealed that the DTH reaction in responders (19+/-6 mm) was stronger than that in non-responders (6+/-4 mm) (p<0.0001). Tumor necrosis factor (TNF)-alpha production of ascites cells was also higher in responders (3943+/-1247 pg/ml) than in non-responders (1217+/-939 pg/ml) (p=0.0002). There was a significant positive correlation (p=0.0085) between the levels of DTH reaction and TNF-alpha production of ascites cells, but not of blood cells. Responders appeared to polarize on the Th1 axis when clinical responses were plotted on Th1-Th2 dimensions according to the cytokine production profiles of TNF-alpha, IFN-gamma, IL-4 and IL-6 of ascites cells. In vitro culture with IL-2 of ascites cells after OK-432 administration demonstrated an almost clonal expansion of CD4+ lymphocytes, which produced TNF-alpha and IFN-gamma, but did not produce IL-4 or IL-6. IL-10 mRNA expression was detectable in ascites cells from non-responders before treatment. These results suggest that the DTH-oriented locoregional administration of OK-432 may be both effective and less toxic in treating malignant ascites from gastric cancer, showing a possibility of the tailored immunotherapy for malignant ascites. Th1 dysfunction exists in the microenvironment of malignant ascites from gastric cancer, in which IL-10 may, in part, play a role. The up-regulation of Th1 responses by OK-432 may result in positive clinical responses. The DTH reaction to OK-432 may be a useful tool not only for predicting clinical response but also for selecting the optimal dose of OK-432.
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan. shogo@hiroshima-u.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Akiko
authors.initials: A
authors.lastname: Ohshita
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawabuchi
authors.forename: Jun
authors.initials: J
authors.lastname: Hihara
authors.forename: Eiji
authors.initials: E
authors.lastname: Miyahara
authors.forename: Kosuke
authors.initials: K
authors.lastname: Noma
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Toge
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001201:Ascites / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D007167:Immunotherapy; D016753:Interleukin-10 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010844:Picibanil / Q000008:administration & dosage*; D010865:Pilot Projects; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000276:immunology / Q000628:therapy*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D010844:Picibanil