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 targetspecificity and high therapeutic activity in patients with cancer. Brentuximab vedotin represents a first-in-class ADC directed against CD30 þ 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 tumordraining 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. Cancer Immunol Res; 2(8); 741-55. Ó2014 AACR.

Antibody–Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review

“…The recent findings of Zippelius et al [92–94] suggest that ADCs, especially those made with the potent microtubule-disrupting agents as the payload, may be combined with immune checkpoint inhibitors such as anti-PD1 antibodies (pembrolizumab, nivolumab) or anti-PD-L1 antibodies (atezolizumab) for enhanced and sustained anti-tumor effect. Not only do such ADCs induce immunogenic cell death, but the ADC-mediated tumor accumulation of a potent microtubule agent appears to activate intra-tumor dendritic cells, inducing uptake of antigens and the migration of antigen-loaded dendritic cells to lymph nodes where they can trigger activation of T-cells which may be directed towards tumor-associated antigens [92–95].…”

Antibody–Drug Conjugates for Cancer Therapy

“…The induction of tumour cell death following ADC therapy may allow the expression of tumour antigens that, in conjunction with the immune checkpoint blockade, facilitate a host T cell response against the tumour. A recent preclinical study has shown that brentuximab vedotin is a potent inducer of dendritic cell (DC) maturation [86]. This study identified that, in addition to the cytotoxic capabilities of this ADC, brentuximab vedotin can stimulate a host adaptive immune response in both patient and animal models.…”

Innovative Treatment Concepts for Cutaneous T-Cell Lymphoma Based on Microenvironment Modulation

“…It was first described in 2003 and acts by binding to CD30 with high affinity, consequently releasing MMAE into the cytosol where it induces cell cycle arrest and apoptosis [25]. Beyond this mechanism of action, there is evolving evidence that MMAE may promote antitumor immunity by activating tumorresident dendritic cells (DCs) [26]. Over a period of 10 years, it has become evident that DCs, besides being potent antigen-presenting cells, occur in the tumor microenvironment as regulatory DCs, contributing to immune evasion by tumors.…”