title: Prolonged recurrence-free survival following OK432-stimulated dendritic cell transfer into hepatocellular carcinoma during transarterial embolization.
abstract: 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.
authors.affiliation: Cancer Research Institute, Kanazawa University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamoto
authors.forename: E
authors.initials: E
authors.lastname: Mizukoshi
authors.forename: M
authors.initials: M
authors.lastname: Kitahara
authors.forename: F
authors.initials: F
authors.lastname: Arihara
authors.forename: Y
authors.initials: Y
authors.lastname: Sakai
authors.forename: K
authors.initials: K
authors.lastname: Kakinoki
authors.forename: Y
authors.initials: Y
authors.lastname: Fujita
authors.forename: Y
authors.initials: Y
authors.lastname: Marukawa
authors.forename: K
authors.initials: K
authors.lastname: Arai
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.forename: N
authors.initials: N
authors.lastname: Mukaida
authors.forename: K
authors.initials: K
authors.lastname: Matsushima
authors.forename: O
authors.initials: O
authors.lastname: Matsui
authors.forename: S
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000628:therapy* / Q000821:virology; D003131:Combined Modality Therapy; D016207:Cytokines / Q000097:blood / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000637:transplantation*; D018572:Disease-Free Survival; D004621:Embolization, Therapeutic; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006526:Hepatitis C / Q000276:immunology; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D015847:Interleukin-4 / Q000494:pharmacology; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000628:therapy* / Q000821:virology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009364:Neoplasm Recurrence, Local / Q000628:therapy; D010844:Picibanil / Q000494:pharmacology*; D011859:Radiography
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D015847:Interleukin-4; D010844:Picibanil; D016178:Granulocyte-Macrophage Colony-Stimulating Factor