Department of Hematology and Medical Oncology.
Institute for Clinical Chemistry, Laboratory Medicine and Transfusion Medicine, Nuremberg General Hospital & Paracelsus Medical University, Nuremberg, Germany.
J Immunother. 2019 Nov/Dec;42(9):331-344. doi: 10.1097/CJI.0000000000000289.
Tumor antigen-targeting monoclonal antibodies (mAbs) are an important element of current cancer therapies. Some of these therapeutic mAbs enable antibody-dependent cell mediated cytotoxicity (ADCC) against tumor cells. However, cancer-related functional impairment of immune effector cells may limit the clinical efficacy of antibody treatments. We reckoned that combining mAbs with cell-based immunotherapies would provide a clinically relevant synergism and benefit for cancer patients. Here, we focus on γδ T cells, as earlier studies demonstrated that γδ T-cell-based therapies are safe and promising for several types of malignancies. Similar to natural killer cells, their antitumor effects can be enhanced using antibodies, and they could, therefore, become a versatile effector cell platform for use with a variety of licensed therapeutic mAbs against cancer. In this study, we explore the potential of a combination therapy of activated γδ T cells with rituximab and the more recently developed mAbs (obinutuzumab and daratumumab) in different B-cell malignancies in vitro. Obinutuzumab outperformed the other mAbs with regard to direct target cell lysis and ADCC by γδ T cells in several CD20 cell lines and primary lymphoma specimens. We demonstrate that comparatively few CD16 γδ T cells are sufficient to mediate a strong ADCC. Using Fc-receptor-positive B-cell lymphomas as target cells, ADCC cannot be blocked by high concentrations of immunoglobulins or anti-CD16 antibodies, but both substances can promote cell mediated target cell lysis. This study expands on earlier reports on the therapeutic potential of distinctive tumor antigen-targeting mAbs and facilitates the understanding of the mechanism and potential of ADCC by γδ T-cell subsets.
肿瘤抗原靶向单克隆抗体（mAbs）是当前癌症治疗的重要组成部分。其中一些治疗性 mAbs 能够诱导肿瘤细胞的抗体依赖的细胞介导的细胞毒性（ADCC）。然而，免疫效应细胞与癌症相关的功能障碍可能会限制抗体治疗的临床疗效。我们推测，将 mAbs 与基于细胞的免疫疗法相结合将为癌症患者提供临床相关的协同作用和益处。在这里，我们重点关注 γδ T 细胞，因为早期的研究表明，基于 γδ T 细胞的疗法对于多种类型的恶性肿瘤是安全且有前景的。与自然杀伤细胞类似，它们的抗肿瘤作用可以通过抗体增强，因此，它们可以成为一种多功能的效应细胞平台，可与针对癌症的各种已获许可的治疗性 mAbs 一起使用。在这项研究中，我们探讨了在体外使用激活的 γδ T 细胞与利妥昔单抗以及最近开发的 mAbs（奥滨尤妥珠单抗和达雷妥尤单抗）联合治疗不同 B 细胞恶性肿瘤的潜力。在几种 CD20 细胞系和原发性淋巴瘤标本中，奥滨尤妥珠单抗在直接靶细胞裂解和 γδ T 细胞介导的 ADCC 方面优于其他 mAbs。我们证明，相对较少数量的 CD16 γδ T 细胞就足以介导强大的 ADCC。使用 Fc 受体阳性 B 细胞淋巴瘤作为靶细胞时，ADCC 不能被高浓度的免疫球蛋白或抗 CD16 抗体阻断，但这两种物质都可以促进细胞介导的靶细胞裂解。这项研究扩展了关于独特肿瘤抗原靶向 mAbs 的治疗潜力的早期报告，并有助于理解 γδ T 细胞亚群的 ADCC 的机制和潜力。
