PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses.
PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses.
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DOI：
10.1126/scitranslmed.3006597
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发表时间：
2013-12-11
影响因子：
17.1
通讯作者：
Sadelain M
中科院分区：
文献类型：
--
作者：
Fedorov VD;Themeli M;Sadelain M
T细胞疗法已在一些癌症的治疗中显示出长期疗效和治愈潜力。然而，其应用受到对旁观组织损伤的限制，比如在供体淋巴细胞输注后的移植物抗宿主病中所见，或者在一些工程化T细胞疗法中出现的“靶向正确但脱靶肿瘤”的毒性。非特异性免疫抑制和不可逆的T细胞清除是目前控制此类有害反应的唯一手段，但这是以消除治疗益处或导致继发性并发症为代价的。基于免疫抑制受体的生理范例，我们设计了抗原特异性抑制性嵌合抗原受体（iCARs）来预先限制T细胞反应。我们证明，基于CTLA - 4或PD - 1的iCARs能够选择性地限制由内源性T细胞受体或激活型嵌合受体诱导的细胞因子分泌、细胞毒性和增殖。iCAR的初始作用是暂时的，因此能使T细胞在随后遇到其激活受体所识别的抗原时发挥作用。因此，iCARs提供了一种动态的、自我调节的安全开关，以预防而非治疗T细胞特异性不足所导致的后果。
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. Non-specific 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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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
影响因子：
17.1
作者：
Amarnath S;Mangus CW;Wang JC;Wei F;He A;Kapoor V;Foley JE;Massey PR;Felizardo TC;Riley JL;Levine BL;June CH;Medin JA;Fowler DH
通讯作者：
Fowler DH
影响因子：
2.6
作者：
Kinoshita, Y;Kuratsukuri, K;Haas, GP
通讯作者：
Haas, GP
影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M