title: Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells.
abstract: Antibody-drug conjugates (ADC) are emerging as powerful treatment strategies with outstanding target-specificity and high therapeutic activity in patients with cancer. Brentuximab vedotin represents a first-in-class ADC directed against CD30(+) malignancies. We hypothesized that its sustained clinical responses could be related to the stimulation of an anticancer immune response. In this study, we demonstrate that the dolastatin family of microtubule inhibitors, from which the cytotoxic component of brentuximab vedotin is derived, comprises potent inducers of phenotypic and functional dendritic cell (DC) maturation. In addition to the direct cytotoxic effect on tumor cells, dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to the tumor-draining lymph nodes. Exposure of murine and human DCs to dolastatins significantly increased their capacity to prime T cells. Underlining the requirement of an intact host immune system for the full therapeutic benefit of dolastatins, the antitumor effect was far less pronounced in immunocompromised mice. We observed substantial therapeutic synergies when combining dolastatins with tumor antigen-specific vaccination or blockade of the PD-1-PD-L1 and CTLA-4 coinhibitory pathways. Ultimately, treatment with ADCs using dolastatins induces DC homing and activates cellular antitumor immune responses in patients. Our data reveal a novel mechanism of action for dolastatins and provide a strong rationale for clinical treatment regimens combining dolastatin-based therapies, such as brentuximab vedotin, with immune-based therapies.
authors.affiliation: Cancer Immunology & Biology, Department of Biomedicine, Departments of alfred.zippelius@usb.ch ph.mueller@unibas.ch.
authors.forename: Philipp
authors.initials: P
authors.lastname: Müller
authors.affiliation: Cancer Immunology & Biology, Department of Biomedicine, Departments of.
authors.forename: Kea
authors.initials: K
authors.lastname: Martin
authors.affiliation: Department I of Internal Medicine and Cologne Interventional Immunology and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Theurich
authors.affiliation: Cancer Immunology & Biology, Department of Biomedicine, Departments of.
authors.forename: Jens
authors.initials: J
authors.lastname: Schreiner
authors.affiliation: Institute of Pathology, University Hospital Basel;
authors.forename: Spasenija
authors.initials: S
authors.lastname: Savic
authors.affiliation: Cancer Immunology & Biology, Department of Biomedicine, Departments of.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Terszowski
authors.affiliation: Surgery.
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.affiliation: Gynecology and Obstetrics, and.
authors.forename: Viola A
authors.initials: VA
authors.lastname: Heinzelmann-Schwarz
authors.affiliation: Department of Dermatology, Skin Cancer Center (CIO), University Hospital Cologne, Cologne; and.
authors.forename: Max
authors.initials: M
authors.lastname: Schlaak
authors.affiliation: Senckenberg Institute of Pathology, University of Frankfurt, Frankfurt, Germany.
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Kvasnicka
authors.affiliation: Department of Biomedicine, Institute of Surgical Research and Hospital Management, University of Basel, Basel;
authors.forename: Giulio
authors.initials: G
authors.lastname: Spagnoli
authors.affiliation: Institute of Pathology, University Hospital Basel;
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland;
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.affiliation: Department I of Internal Medicine and Cologne Interventional Immunology and.
authors.forename: Michael
authors.initials: M
authors.lastname: von Bergwelt-Baildon
authors.affiliation: Cancer Immunology & Biology, Department of Biomedicine, Departments of Medical Oncology, alfred.zippelius@usb.ch ph.mueller@unibas.ch.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000941:Antigens / Q000276:immunology; D000079963:Brentuximab Vedotin; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D019496:Cancer Vaccines / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D047630:Depsipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D010047:Ovalbumin / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D050257:Tubulin Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000906:Antibodies; D000941:Antigens; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D016207:Cytokines; D047630:Depsipeptides; D018796:Immunoconjugates; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D050257:Tubulin Modulators; C075610:dolastatin 15; D000079963:Brentuximab Vedotin; D010047:Ovalbumin; C064570:dolastatin 10