Combining antibody–drug conjugates and immune-mediated cancer therapy: What to expect?

免疫检查点 细胞毒性T细胞 免疫系统 CD8型 封锁 癌症 癌症研究 T细胞 效应器 医学 抗体 免疫疗法 免疫学 生物 内科学 体外 受体 生物化学
作者
Hans‐Peter Gerber,Puja Sapra,Frank Loganzo,Chad May
出处
期刊:Biochemical Pharmacology [Elsevier]
卷期号:102: 1-6 被引量:124
标识
DOI:10.1016/j.bcp.2015.12.008
摘要

Blockade of immune-checkpoints has emerged as one of the most promising approaches to improve the durability of anti-tumor responses in cancer patients. However, the fraction of patients experiencing durable responses to single agent immune checkpoint inhibitor treatment remains limited. Recent clinical reports suggest that patients responding best to checkpoint blockade therapies display higher levels of CD8(+) T-cells in the tumor prior to treatment. Therefore, combination treatments of immune-checkpoint inhibitors with compounds that increase the number of tumor infiltrating CD8(+) T cells may expand the therapeutic benefit of immuno-oncology (IO) drugs. Immunogenic cell death (ICD) of tumor cells is induced by certain classes of cytotoxic compounds and represents a potent stimulator of effector T-cell recruitment to tumors. In addition, several cytotoxics directly stimulate dendritic cell activation and maturation, resulting in improved anti-tumor immune responses when combined with IO compounds. Among them, several cytotoxic agents are currently utilized as payloads for antibody-drug conjugates (ADCs). Therefore, identification of optimal combination regimens between ADC- and IO compounds holds strong promise to overcome the current limitations of immune checkpoint inhibitors, by increasing the recruitment of CD8(+) effector T-cells to the tumor core. Here we review the emerging field of ADC/IO combination research, with a focus on how to optimally combine both modalities. The answer to this question may have a broader impact on oncology drug development, as synergistic activities between IO compounds and ADCs may increase the formation of tumor specific immunological memory, ultimately leading to durable responses in a larger fraction of cancer patients.
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