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Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells.
- Source :
-
Cancer immunology research [Cancer Immunol Res] 2014 Aug; Vol. 2 (8), pp. 741-55. Date of Electronic Publication: 2014 Apr 21. - Publication Year :
- 2014
-
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.<br /> (©2014 American Association for Cancer Research.)
- Subjects :
- Animals
Antibodies therapeutic use
Antigens immunology
Brentuximab Vedotin
CTLA-4 Antigen antagonists & inhibitors
Cancer Vaccines therapeutic use
Cell Line
Cells, Cultured
Cytokines immunology
Dendritic Cells cytology
Dendritic Cells drug effects
Depsipeptides therapeutic use
Humans
Immunoconjugates therapeutic use
Mice, Inbred C57BL
Mice, Transgenic
Neoplasms pathology
Neoplasms therapy
Ovalbumin immunology
Programmed Cell Death 1 Receptor antagonists & inhibitors
T-Lymphocytes drug effects
T-Lymphocytes immunology
Tubulin Modulators therapeutic use
Tumor Burden drug effects
Dendritic Cells immunology
Depsipeptides pharmacology
Neoplasms immunology
Tubulin Modulators pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2326-6074
- Volume :
- 2
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cancer immunology research
- Publication Type :
- Academic Journal
- Accession number :
- 24916470
- Full Text :
- https://doi.org/10.1158/2326-6066.CIR-13-0198