嵌合抗原受体
免疫疗法
T细胞
旁观者效应
免疫学
抗原
免疫抑制
癌症研究
受体
免疫系统
生物
医学
内科学
作者
V D Fedorov,Maria Themeli,Michel Sadelain
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2013-12-11
卷期号:5 (215)
被引量:613
标识
DOI:10.1126/scitranslmed.3006597
摘要
T cell therapies have demonstrated long-term efficacy and curative potential for the treatment of some cancers. However, their use is limited by damage to bystander tissues, as seen in graft-versus-host disease after donor lymphocyte infusion, or "on-target, off-tumor" toxicities incurred in some engineered T cell therapies. Nonspecific immunosuppression and irreversible T cell elimination are currently the only means to control such deleterious responses, but at the cost of abrogating therapeutic benefits or causing secondary complications. On the basis of the physiological paradigm of immune inhibitory receptors, we designed antigen-specific inhibitory chimeric antigen receptors (iCARs) to preemptively constrain T cell responses. We demonstrate that CTLA-4- or PD-1-based iCARs can selectively limit cytokine secretion, cytotoxicity, and proliferation induced through the endogenous T cell receptor or an activating chimeric receptor. The initial effect of the iCAR is temporary, thus enabling T cells to function upon a subsequent encounter with the antigen recognized by their activating receptor. iCARs thus provide a dynamic, self-regulating safety switch to prevent, rather than treat, the consequences of inadequate T cell specificity.
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