title: Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts.
abstract: The selective delivery of bioactive agents to tumors reduces toxicity and enhances the efficacy of anticancer therapies. In this study, we show that the antibody F8, which recognizes perivascular and stromal EDA-fibronectin (EDA-Fn), when conjugated to interleukin-2 (F8-IL2) can effectively inhibit the growth of EDA-Fn-expressing melanomas in combination with paclitaxel. We obtained curative effects with paclitaxel administered before the immunocytokine. Coadministration of paclitaxel increased the uptake of F8 in xenografted melanomas, enhancing tumor perfusion and permeability. Paclitaxel also boosted the recruitment of F8-IL2-induced natural killer (NK) cells to the tumor, suggesting a host response as part of the observed therapeutic benefit. In support of this likelihood, NK cell depletion impaired the antitumor effect of paclitaxel plus F8-IL2. Importantly, this combination reduced both the tumor burden and the number of pulmonary metastatic nodules. The combination did not cause cumulative toxicity. Together, our findings offer a preclinical proof that by acting on the tumor stroma paclitaxel potentiates the antitumor activity elicited by a targeted delivery of IL2, thereby supporting the use of immunochemotherapy in the treatment of metastatic melanoma.
authors.affiliation: Departments of Oncology, Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.forename: Francesca
authors.initials: F
authors.lastname: Pretto
authors.forename: Alexander
authors.initials: A
authors.lastname: Berndt
authors.forename: Kerstin
authors.initials: K
authors.lastname: Galler
authors.forename: Petra
authors.initials: P
authors.lastname: Richter
authors.forename: Andrea
authors.initials: A
authors.lastname: Bassi
authors.forename: Paolo
authors.initials: P
authors.lastname: Oliva
authors.forename: Edoardo
authors.initials: E
authors.lastname: Micotti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Valbusa
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwager
authors.forename: Manuela
authors.initials: M
authors.lastname: Kaspar
authors.forename: Eveline
authors.initials: E
authors.lastname: Trachsel
authors.forename: Hartwig
authors.initials: H
authors.lastname: Kosmehl
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Bani
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
authors.forename: Raffaella
authors.initials: R
authors.lastname: Giavazzi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D005353:Fibronectins / Q000032:analysis*; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D020033:Protein Isoforms; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; C528643:F8 monoclonal antibody; D005353:Fibronectins; D007376:Interleukin-2; D020033:Protein Isoforms; D017239:Paclitaxel