Molecular Pathways: Breaking the Epithelial Cancer Barrier for Chimeric Antigen Receptor and T-cell Receptor Gene Therapy.
Molecular Pathways: Breaking the Epithelial Cancer Barrier for Chimeric Antigen Receptor and T-cell Receptor Gene Therapy.
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分子途径：打破嵌合抗原受体和T细胞受体基因治疗的上皮癌屏障。
DOI：
10.1158/1078-0432.ccr-15-1294
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发表时间：
2016-04-01
期刊：
影响因子：
--
通讯作者：
Hinrichs CS
中科院分区：
文献类型：
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作者：
Hinrichs CS
遗传工程化以表达肿瘤靶向嵌合抗原受体（CAR）或T细胞受体（CAR）的T细胞的连续转移可以介导一些患者的癌症消退。CAR是采用抗体结构域靶向细胞表面抗原的合成单链蛋白。TCR是天然的异源二聚体蛋白，其可以通过识别与人白细胞抗原结合的肽来靶向细胞内抗原。CAR在B细胞恶性肿瘤和黑色素瘤中的TCR中显示出前景，但这两种方法都没有在上皮癌中取得明显的成功。上皮癌的治疗可能是特别具有挑战性的，因为缺乏由癌而不是由重要的健康组织表达的靶抗原。此外，上皮癌可以通过肿瘤微环境中的抑制性配体和可溶性因子来保护。克服这些负调节因子的一种策略是调节T细胞基因的表达以增强内在T细胞功能。可抑制抑制性基因的可编程核酸酶和可增强刺激性基因的诱导性基因表达系统正在进入临床测试。其他工作是描述免疫检查点受体（例如PDCD 1，CTLA 4）和细胞因子和TCR信号转导调节因子（例如CBLB，CISH，IL 12，IL 15）的基因控制是否可以增加治疗性T细胞的抗肿瘤活性。
Adoptive transfer of T cells genetically engineered to express a tumor-targeting chimeric antigen receptor (CAR) or T cell receptor (CAR) can mediate cancer regression in some patients. CARs are synthetic single chain proteins that employ antibody domains to target cell surface antigens. TCRs are natural heterodimeric proteins that can target intracellular antigens through recognition of peptides bound to human leukocyte antigens. CARs have shown promise in B cell malignancies and TCRs in melanoma, but neither approach has achieved clear success in an epithelial cancer. Treatment of epithelial cancers may be particularly challenging because of a paucity of target antigens expressed by carcinomas and not by important healthy tissues. In addition, epithelial cancers may be protected by inhibitory ligands and soluble factors in the tumor microenvironment. One strategy to overcome these negative regulators is to modulate expression of T cell genes to enhance intrinsic T cell function. Programmable nucleases, which can suppress inhibitory genes, and inducible gene expression systems, which can enhance stimulatory genes are entering clinical testing. Other work is delineating whether control of genes for immune checkpoint receptors (e.g. PDCD1, CTLA4), and cytokine and TCR signaling regulators (e.g. CBLB, CISH, IL12, IL15) can increase the anti-tumor activity of therapeutic T cells.