Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity.
Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity.
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DOI：
10.1038/s41598-017-14749-3
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发表时间：
2017-10-30
影响因子：
4.6
通讯作者：
Jin MM
中科院分区：
文献类型：
--
作者：
Park S;Shevlin E;Vedvyas Y;Zaman M;Park S;Hsu YS;Min IM;Jin MM
针对血液系统肿瘤的高亲和力嵌合抗原受体(CAR)T细胞过继转移已经取得了令人印象深刻的临床结果。然而，对健康组织靶向表达的安全性担忧和较差的疗效阻碍了其在实体肿瘤中的应用。在这里，利用其生理配体LFA-1构建了一组针对过表达的ICAM-1的亲和力变异CARS，ICAM-1是一种广泛的肿瘤生物标记物。体外抗肿瘤T细胞活性与CAR亲和力和ICAM-1浓度成正比。在可以同时监测抗肿瘤效力和全身非肿瘤毒性的实体瘤小鼠模型中，微摩尔亲和力CAR T细胞显示出比其纳米分子对应细胞更优越的抗肿瘤效果和安全性。PET/CT纵向T细胞示踪和细胞因子同步检测显示微摩尔亲和力CAR T细胞具有优越的扩张和收缩动力学。因此，我们开发了一种具有广泛抗肿瘤适用性的ICAM-1特异性CAR，它利用降低亲和力的靶向策略显著提高了疗效和安全性。
Adoptive transfer of high-affinity chimeric antigen receptor (CAR) T cells targeting hematological cancers has yielded impressive clinical results. However, safety concerns regarding target expression on healthy tissue and poor efficacy have hampered application to solid tumors. Here, a panel of affinity-variant CARs were constructed targeting overexpressed ICAM-1, a broad tumor biomarker, using its physiological ligand, LFA-1. Anti-tumor T cell potency in vitro was directly proportional to CAR affinity and ICAM-1 density. In a solid tumor mouse model allowing simultaneous monitoring of anti-tumor potency and systemic off-tumor toxicity, micromolar affinity CAR T cells demonstrated superior anti-tumor efficacy and safety compared to their nanomolar counterparts. Longitudinal T cell tracking by PET/CT and concurrent cytokine measurement revealed superior expansion and contraction kinetics of micromolar affinity CAR T cells. Therefore, we developed an ICAM-1 specific CAR with broad anti-tumor applicability that utilized a reduced affinity targeting strategy to significantly boost efficacy and safety.
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DOI：
10.1084/jem.20061890
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Boissonnas A;Fetler L;Zeelenberg IS;Hugues S;Amigorena S
通讯作者：
Amigorena S
影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
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
DOI：
10.2967/jnumed.109.066902
发表时间：
2010-03
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Laverman P;McBride WJ;Sharkey RM;Eek A;Joosten L;Oyen WJ;Goldenberg DM;Boerman OC
通讯作者：
Boerman OC
影响因子：
5.1
作者：
Kang, S.;Lu, K.;Jin, M. M.
通讯作者：
Jin, M. M.