Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel.
Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel.
Drug Resist Updat. 2017 Jan;30:39-47. doi: 10.1016/j.drup.2017.02.001. Epub 2017 Feb 4.
Drug resistance of tumor cells to chemotherapy is limiting the therapeutic efficacy of most anticancer drugs and represents a major obstacle in medical oncology. However, treatment of various human malignancies with biologics, mostly monoclonal antibodies (mAbs), is not limited by such chemoresistance mechanisms. However, other resistance or evasion mechanisms limit the efficacy to anticancer therapeutic mAbs that engage tumor-associated antigens on the surface of the malignant cells. Immune checkpoint blocking monoclonal antibodies are heralded as a promising therapeutic approach in clinical oncology. These mAbs do not directly attack the malignant cells as most anticancer mAbs; rather, they enhance the anti-tumor response of the immune system by targeting immune regulatory pathways. Three mAbs targeting immune checkpoint molecules are currently used in the clinic and new mAbs that target other potential inhibitory targets are being actively investigated. This therapeutic approach, while proving as highly beneficial for many patients, is prone to toxicities and side effects of an autoimmune nature. Defining suitable management algorithms and biomarkers that predict therapeutic effects and adverse toxicity are required to provide survival benefit for larger numbers of cancer patients. Overcoming these challenges, along with opportunities for new agents and combinatorial strategies are the main focus of immune checkpoint blockade research today.
肿瘤细胞对化疗的耐药性限制了大多数抗癌药物的治疗效果，是肿瘤医学中的主要障碍。然而，生物制剂（主要是单克隆抗体）治疗各种人类恶性肿瘤不受这种化疗耐药机制的限制。然而，其他耐药或逃避机制限制了与肿瘤相关抗原结合的抗癌治疗性单克隆抗体的疗效，这些抗原存在于恶性细胞的表面。免疫检查点阻断单克隆抗体被认为是临床肿瘤学中一种很有前途的治疗方法。这些单克隆抗体不像大多数抗癌单克隆抗体那样直接攻击恶性细胞；相反，它们通过靶向免疫调节途径来增强免疫系统的抗肿瘤反应。目前有 3 种针对免疫检查点分子的单克隆抗体在临床上使用，并且正在积极研究针对其他潜在抑制靶点的新单克隆抗体。这种治疗方法虽然对许多患者非常有益，但容易产生自身免疫性质的毒性和副作用。需要定义合适的管理算法和预测治疗效果和不良毒性的生物标志物，为更多癌症患者提供生存获益。克服这些挑战，以及新药物和联合策略的机会，是当今免疫检查点阻断研究的主要重点。
