title: Local immunostimulation induced by intravesical administration of autologous interferon-gamma-activated macrophages in patients with superficial bladder cancer.
abstract: We conducted a phase I/II clinical trial of the safety and efficacy of intravesical administration of autologous IFN-gamma-activated macrophages (MAK) in patients with superficial bladder cancer. Monocyte-derived MAK cells were prepared in vitro and patients received six instillations of 1.4 x 10(8) to 2.5 x 10(8) cells, once a week, for five consecutive weeks. Treatment was well tolerated, with seven grade 1 and five Grade 2 protocol-related adverse effects. Nine out of 17 included patients had no recurrences during the year following the first instillation of MAK. The aim of the present study was to search for immune parameters related to local immunostimulation induced by MAK. Monitoring of the patients showed that urinary IL-8, GM-CSF and, to a lesser extent, IL-18 were increased following MAK instillations, with inter-individual differences. The urinary IL-8 level was about 10-fold higher than that observed for other cytokines, and its biological activity was reflected by a concomitant increase of urinary elastase, indicating neutrophil activation and degranulation. We also showed that nine out of 12 patients investigated presented an increase of urinary neopterin, a marker of IFN-gamma-activated macrophages, 7 days after MAK instillation, while serum neopterin levels were almost stable. These results are in line with persistence of activated macrophages in the bladder wall after infusions. Moreover, there was evidence of macrophages in urine smears 2 months after the sixth MAK instillation, and the score of macrophages correlated with the quantity of neutrophils in the urine. Overall, this study provides evidence of a local immunostimulation induced by this novel and safe immunotherapeutic approach of MAK instillations in patients with superficial bladder cancer.
authors.affiliation: Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique, Unité INSERM 255, France. Franck.PAGES@hop.egp.ap-hop-paris.fr
authors.forename: F
authors.initials: F
authors.lastname: Pagès
authors.forename: S
authors.initials: S
authors.lastname: Lebel-Binay
authors.forename: A
authors.initials: A
authors.lastname: Vieillefond
authors.forename: L
authors.initials: L
authors.lastname: Deneux
authors.forename: M
authors.initials: M
authors.lastname: Cambillau
authors.forename: O
authors.initials: O
authors.lastname: Soubrane
authors.forename: B
authors.initials: B
authors.lastname: Debré
authors.forename: D
authors.initials: D
authors.lastname: Tardy
authors.forename: J-L Romet
authors.initials: JL
authors.lastname: Lemonne
authors.forename: J-P
authors.initials: JP
authors.lastname: Abastado
authors.forename: W-H
authors.initials: WH
authors.lastname: Fridman
authors.forename: N
authors.initials: N
authors.lastname: Thiounn
mesh_terms: D000283:Administration, Intravesical; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D015415:Biomarkers; D014408:Biomarkers, Tumor; D002452:Cell Count; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000652:urine; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000494:pharmacology*; D007378:Interleukins / Q000652:urine; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism; D009363:Neoplasm Proteins / Q000032:analysis; D009364:Neoplasm Recurrence, Local; D019798:Neopterin / Q000032:analysis; D009504:Neutrophils; D012449:Safety; D014409:Tumor Necrosis Factor-alpha / Q000652:urine; D001749:Urinary Bladder Neoplasms / Q000628:therapy*; D014556:Urine / Q000166:cytology; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D014408:Biomarkers, Tumor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D007378:Interleukins; D009363:Neoplasm Proteins; D019798:Neopterin; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule