Microtubule-Depolymerizing Agents Used in Antibody-Drug Conjugates Induce Antitumor Immunity by Stimulation of Dendritic Cells
Microtubule-Depolymerizing Agents Used in Antibody-Drug Conjugates Induce Antitumor Immunity by Stimulation of Dendritic Cells
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DOI：
10.1158/2326-6066.cir-13-0198
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发表时间：
2014-08-01
影响因子：
10.1
通讯作者：
Zippelius, Alfred
中科院分区：
文献类型：
--
作者：
Mueller, Philipp;Martin, Kea;Zippelius, Alfred
抗体-药物偶联物（ADC）是一种新型的治疗药物，具有靶向特异性强、治疗活性高的特点。维布妥昔单抗代表了针对CD 30（+）恶性肿瘤的一流ADC。我们推测其持续的临床反应可能与刺激抗癌免疫反应有关。在本研究中，我们证明了微管抑制剂多拉司他汀家族（维布妥昔单抗的细胞毒性组分来源于此）包含表型和功能性树突状细胞（DC）成熟的强效诱导剂。除了对肿瘤细胞的直接细胞毒性作用外，多拉司他汀有效地促进抗原摄取和肿瘤驻留DC向肿瘤引流淋巴结的迁移。鼠和人DC暴露于多拉司他汀显著增加了它们致敏T细胞的能力。强调完整的宿主免疫系统对于多拉司他汀的全部治疗益处的要求，抗肿瘤作用在免疫受损小鼠中远不明显。当将多拉司他汀与肿瘤抗原特异性疫苗接种或阻断PD-1-PD-L1和CTLA-4共抑制途径组合时，我们观察到显著的治疗协同作用。最终，使用多拉司他汀的ADC治疗诱导DC归巢并激活患者的细胞抗肿瘤免疫应答。我们的数据揭示了多拉司他汀的一种新的作用机制，并为基于多拉司他汀的治疗（如维布妥昔单抗）与基于免疫的治疗相结合的临床治疗方案提供了强有力的依据。(C)2014年AACR。
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.