title: Dendritic cell-based immunotherapy in prevention and treatment of renal cell carcinoma: efficacy, safety, and activity of Ad-GM·CAIX in immunocompetent mouse models.
abstract: The dendritic cell vaccine DC-Ad-GM·CAIX is an active, specific immunotherapy with the potential of providing a safe and effective therapy against renal cell carcinoma (RCC). Using immunocompetent Balb/c mouse models we tested the efficacy and mechanism of the vaccine to prevent and treat the growth of a syngeneic RCC (RENCA) engineered to overexpress the human TAA carbonic anhydrase IX (NPR-IX). In a prevention model, NPR-IX tumor development was specifically and significantly delayed by 13 days in DC-Ad-GM·CAIX-treated mice (P < 0.001), tumor volumes were 79% smaller (day 24, P < 0.007), and body weight was maintained at study termination compared with the controls. Six of these mice remained tumor-free for > 1 year. In a treatment model, NPR-IX tumors remained smaller in DC-Ad-GM·CAIX-treated mice for 8 days (P < 0.002), achieving a 60% growth inhibition at termination. No vaccine-related organ toxicity was observed in either model. The critical mechanistic parameter separating responsive from nonresponsive tumors was hCAIX protein expression, demonstrated by aggressive growth of tumors that did not express hCAIX protein and in sham-treated mice (DC-Ad-Null). No murine serum anti-hCAIX antibodies were detected. Moreover, altered mechanisms of immunoediting as a means for immune evasion were suggested by differential gene expression (Ccl1, Hmgb1, Fgl2, Cd209a, and Klra2) and therapy evasion miRNAs (miR-1186, miR-98, miR-5097, miR-1942, and miR-708) in tumors that evaded DC-Ad-GM·CAIX immunotherapy. This is the first study in immunocompetent mice that provides a proof of concept for the specificity, efficacy, safety, and activity of the DC-Ad-GM·CAIX immunotherapy, forming the basis for a first-in-human phase I trial in RCC patients.
authors: Institute of Urologic Oncology, David Geffen School of Medicine at the University of California, Los Angeles, CA 90024, USA.
authors: Frédéric D
authors: FD
authors: Birkhäuser
authors: Richard C
authors: RC
authors: Koya
authors: Caleb
authors: C
authors: Neufeld
authors: Edward N
authors: EN
authors: Rampersaud
authors: Xuyang
authors: X
authors: Lu
authors: Ewa D
authors: ED
authors: Micewicz
authors: Thinle
authors: T
authors: Chodon
authors: Mohammad
authors: M
authors: Atefi
authors: Nils
authors: N
authors: Kroeger
authors: Gadisetti V R
authors: GV
authors: Chandramouli
authors: Gang
authors: G
authors: Li
authors: Jonathan W
authors: JW
authors: Said
authors: William H
authors: WH
authors: McBride
authors: Fairooz F
authors: FF
authors: Kabbinavar
authors: Antoni
authors: A
authors: Ribas
authors: Allan J
authors: AJ
authors: Pantuck
authors: Arie S
authors: AS
authors: Belldegrun
authors: Joseph
authors: J
authors: Riss
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000096:biosynthesis / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D045744:Cell Line, Tumor; D054402:Chemokine CCL1 / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005340:Fibrinogen / Q000096:biosynthesis; D015870:Gene Expression; D016219:Immunotherapy, Adoptive; D007680:Kidney Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D037181:Lectins, C-Type / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000906:Antibodies; D019496:Cancer Vaccines; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D015815:Cell Adhesion Molecules; D054402:Chemokine CCL1; D005340:Fibrinogen; D037181:Lectins, C-Type; D035683:MicroRNAs; D055650:NK Cell Lectin-Like Receptor Subfamily A; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C502258:Ccl1 protein, mouse; C490637:Fgl2 protein, mouse; C527090:Klra2 protein, mouse; C492796:Car9 protein, mouse
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