Mueller, Philipp, Martin, Kea, Theurich, Sebastian ORCID: 0000-0001-5706-8258, Schreiner, Jens, Savic, Spasenija, Terszowski, Grzegorz, Lardinois, Didier, Heinzelmann-Schwarz, Viola A., Schlaak, Max, Kvasnicka, Hans-Michael, Spagnoli, Giulio, Dirnhofer, Stephan, Speiser, Daniel E., von Bergwelt-Baildon, Michael and Zippelius, Alfred (2014). Microtubule-Depolymerizing Agents Used in Antibody-Drug Conjugates Induce Antitumor Immunity by Stimulation of Dendritic Cells. Cancer Immunol. Res., 2 (8). S. 741 - 756. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2326-6074

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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. (C) 2014 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mueller, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, KeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Theurich, SebastianUNSPECIFIEDorcid.org/0000-0001-5706-8258UNSPECIFIED
Schreiner, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savic, SpasenijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Terszowski, GrzegorzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lardinois, DidierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinzelmann-Schwarz, Viola A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlaak, MaxUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kvasnicka, Hans-MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spagnoli, GiulioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dirnhofer, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speiser, Daniel E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Bergwelt-Baildon, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zippelius, AlfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-433187
DOI: 10.1158/2326-6066.CIR-13-0198
Journal or Publication Title: Cancer Immunol. Res.
Volume: 2
Number: 8
Page Range: S. 741 - 756
Date: 2014
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 2326-6074
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BRENTUXIMAB VEDOTIN; ANTINEOPLASTIC AGENTS; HODGKIN LYMPHOMA; CANCER; MECHANISM; SAFETY; DEATH; DIFFERENTIATION; IMMUNOTHERAPY; VINBLASTINEMultiple languages
Oncology; ImmunologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43318

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