Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA.
Department of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, USA.
Sci Rep. 2017 Oct 30;7(1):14366. doi: 10.1038/s41598-017-14749-3.
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.
嵌合抗原受体 (CAR) T 细胞靶向血液系统恶性肿瘤的过继转移取得了令人瞩目的临床效果。然而，由于对健康组织中靶标的表达的安全性的担忧和疗效不佳，该方法在实体瘤中的应用受到了限制。在此，我们构建了一组针对过度表达的细胞间黏附分子-1 (ICAM-1) 的亲和力变异型 CAR，ICAM-1 是一种广泛的肿瘤生物标志物，使用其生理配体 LFA-1。体外抗瘤 T 细胞的效力与 CAR 的亲和力和 ICAM-1 的密度直接成正比。在允许同时监测抗肿瘤效力和系统脱靶毒性的实体瘤小鼠模型中，与纳摩尔亲和力的 CAR T 细胞相比，具有微摩尔亲和力的 CAR T 细胞显示出更好的抗肿瘤疗效和安全性。通过 PET/CT 进行的纵向 T 细胞跟踪和同时进行的细胞因子测量显示，具有微摩尔亲和力的 CAR T 细胞具有更好的扩增和收缩动力学。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，该 CAR 采用了降低亲和力的靶向策略，显著提高了疗效和安全性。
