picibanil and Hepatitis-C

Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0·1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 10⁶ of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0·046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Combined Modality Therapy; Cytokines; Dendritic Cells; Disease-Free Survival; Embolization, Therapeutic; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hepatitis C; Humans; Immunotherapy, Active; Interleukin-4; Liver Neoplasms; Male; Middle Aged; Monocytes; Neoplasm Recurrence, Local; Picibanil; Radiography

We obtained peripheral blood mononuclear cells from 12 chronic hepatitis Type B patients, 12 Type C patients, and 15 healthy volunteers, and investigated the effects of OK-432, a streptococcal preparation, on in vitro production of 3 types of cytokines. Mononuclear cells in a concentration of 1 x 10(6) cell/ml were prepared in the culture medium. OK-432 (Chugai Pharmaceutical Co., Ltd., Tokyo) was added to this preparation and incubated for one to 4 days. Thereafter interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) levels in the culture supernatant were measured using enzyme-linked immunoassay kits. Cytokine production levels in cultures with OK-432 were significantly increased in the mononuclear cells of both patients and healthy volunteers. The largest increase was observed with IFN-gamma (p < 0.01), and then with IL-1 beta (p < 0.05). Responses of the cells from chronic hepatitis Type C patients to OK-432 were relatively good. When interferon (alpha and beta) treatment was first introduced, there were high hopes for a high efficacy. However, we now know 50-70% of patients with chronic hepatitis Type C do not respond satisfactorily to interferon. Some physicians suggest the necessity of using biological response modifier (BRM) as an adjuvant treatment for these patients. From our findings, OK-432 could be a useful BRM in patients with chronic hepatitis Type C.

Topics: Cells, Cultured; Chronic Disease; Cytokines; Enzyme-Linked Immunosorbent Assay; Hepatitis B; Hepatitis C; Humans; Immunologic Factors; Interferon-gamma; Interleukin-1; Interleukin-6; Leukocytes, Mononuclear; Picibanil; Streptococcus

Topics: Adjuvants, Immunologic; Adult; Aged; Biological Products; Chronic Disease; Drug Evaluation; Drug Therapy, Combination; Female; Hepatitis C; Hepatitis, Viral, Human; Humans; Interferon Type I; Liver; Male; Middle Aged; Picibanil; Pilot Projects; Recombinant Proteins

Topics: Adjuvants, Immunologic; Adult; Alanine Transaminase; Biological Products; Drug Evaluation; Female; Hepatitis C; Hepatitis, Chronic; Hepatitis, Viral, Human; Humans; Liver; Male; Middle Aged; Picibanil