title: Intravesical immunotherapy of superficial bladder cancer with chitosan/interleukin-12.
abstract: Intravesical BCG has been used successfully to treat superficial bladder cancer for three decades. However, 20% to 30% of patients will fail initial BCG therapy and 30% to 50% of patients will develop recurrent tumors within 5 years. Alternative or complementary strategies for the management of superficial bladder cancer are needed. Interleukin-12 (IL-12) is a potent T(H)1 cytokine with robust antitumor activity and the ability to potentiate immunologic memory. Unfortunately, intravesical IL-12 did not show antitumor efficacy in a recent clinical study of patients with recurrent superficial bladder cancer. We hypothesized that coformulation of IL-12 with chitosan, a biocompatible, mucoadhesive polysaccharide, could improve intravesical IL-12 delivery and provide an effective and durable alternative for the treatment of superficial bladder cancer. In antitumor studies, 88% to 100% of mice bearing orthotopic bladder tumors were cured after four intravesical treatments with chitosan/IL-12. In contrast, only 38% to 60% of mice treated with IL-12 alone and 0% treated with BCG were cured. Antitumor responses following chitosan/IL-12 treatments were durable and provided complete protection from intravesical tumor rechallenge. Urinary cytokine analysis showed that chitosan/IL-12 induced multiple T(H)1 cytokines at levels significantly higher than either IL-12 alone or BCG. Immunohistochemistry revealed moderate to intense tumor infiltration by T cells and macrophages following chitosan/IL-12 treatments. Bladder submucosa from cured mice contained residual populations of immune cells that returned to baseline levels after several months. Intravesical chitosan/IL-12 is a well-tolerated, effective immunotherapy that deserves further consideration for testing in humans for the management of superficial bladder cancer.
authors.affiliation: Laboratory of Tumor Immunology Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Zaharoff
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Hoffman
authors.forename: H Brooks
authors.initials: HB
authors.lastname: Hooper
authors.forename: Compton J
authors.initials: CJ
authors.lastname: Benjamin
authors.forename: Kiranpreet K
authors.initials: KK
authors.lastname: Khurana
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Hance
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Rogers
authors.forename: Peter A
authors.initials: PA
authors.lastname: Pinto
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: John W
authors.initials: JW
authors.lastname: Greiner
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D048271:Chitosan / Q000008:administration & dosage*; D005260:Female; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000097:blood / Q000652:urine; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000097:blood / Q000652:urine; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*
chemical_list: D001500:BCG Vaccine; D018664:Interleukin-12; D007371:Interferon-gamma; D048271:Chitosan; D008156:Luciferases