肿瘤细胞治疗研究
英文原题：A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo.
这些数据支持将CEA Tmod构建体作为结直肠癌治疗候选药物进行进一步开发。
CEACAM5 基因产物[癌胚抗原(CEA)]是结直肠癌的一个有吸引力的靶点，因为它在几乎所有结直肠肿瘤中高表达，而在大多数健康成人组织中表达有限。然而，据报道，高活性的 CEA 导向研究性治疗药物具有毒性，会因 CEA 在正常肠道上皮细胞上表达而导致严重结肠炎。在此，我们开发了一种解决这一毒性问题的策略：Tmod 双信号整合器。CEA Tmod 细胞使用两种受体：一种由 CEA 激活的嵌合抗原受体(CAR)，以及一种由人类白细胞抗原(HLA)-A*02 触发的基于白细胞 Ig 样受体 1(LIR-1)的抑制性受体。CEA Tmod 细胞利用肿瘤中 HLA 杂合性基因丢失的情况，保护患者免受靶向、脱肿瘤毒性。CEA Tmod 细胞在体外和体内均能强效杀伤表达 CEA 的肿瘤细胞。但与传统的 CEA 特异性 T 细胞受体转基因 T 细胞相比，Tmod 细胞即使与表达 HLA-A*02 的细胞混合，也对肿瘤细胞具有高度选择性。这些数据支持进一步开发 CEA Tmod 构建体作为结直肠癌的治疗候选物。
The CEACAM5 gene product [carcinoembryonic antigen (CEA)] is an attractive target for colorectal cancer because of its high expression in virtually all colorectal tumors and limited expression in most healthy adult tissues. However, highly active CEA-directed investigational therapeutics have been reported to be toxic, causing severe colitis because CEA is expressed on normal gut epithelial cells. Here, we developed a strategy to address this toxicity problem: the Tmod dual-signal integrator. CEA Tmod cells use two receptors: a chimeric antigen receptor (CAR) activated by CEA and a leukocyte Ig-like receptor 1 (LIR-1)-based inhibitory receptor triggered by human leukocyte antigen (HLA)-A*02. CEA Tmod cells exploit instances of HLA heterozygous gene loss in tumors to protect the patient from on-target, off-tumor toxicity. CEA Tmod cells potently killed CEA-expressing tumor cells in vitro and in vivo. But in contrast to a traditional CEA-specific T cell receptor transgenic T cell, Tmod cells were highly selective for tumor cells even when mixed with HLA-A*02-expressing cells. These data support further development of the CEA Tmod construct as a therapeutic candidate for colorectal cancer.
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