Antibody drug conjugates (ADCs) are emerging as powerful treatment strategies with outstanding target specificity and high therapeutic activity in cancer patients. Brentuximab vedotin represents a first-in-class ADC directed against CD30-positive malignancies. We hypothesized that its sustained clinical responses could be related to the stimulation of an anti-cancer immune response. We here 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 DC maturation. In addition to the direct cytotoxic effect on tumor cells, dolastatins efficiently promoted antigen uptake and migration of tumor-resident DCs to 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 anti-tumor effect was far less pronounced in immune-compromised mice. When combining dolastatins with tumor-antigen-specific vaccination or blockade of the PD-1/PD-L1 and CTLA-4 co-inhibitory pathways, we observed substantial therapeutic synergies. Ultimately, ADCs using dolastatins induce DC homing and activate cellular anti-tumor 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.
- Received November 8, 2013.
- Revision received March 24, 2014.
- Accepted April 4, 2014.
- Copyright © 2014, American Association for Cancer Research.