Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.
Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.
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DOI：
10.1080/2162402x.2017.1380764
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Forman SJ
中科院分区：
文献类型：
--
作者：
Priceman SJ;Gerdts EA;Tilakawardane D;Kennewick KT;Murad JP;Park AK;Jeang B;Yamaguchi Y;Yang X;Urak R;Weng L;Chang WC;Wright S;Pal S;Reiter RE;Wu AM;Brown CE;Forman SJ
鉴于最近在血液恶性肿瘤中令人印象深刻的临床应答，推进嵌合抗原受体（CAR）工程化过继T细胞用于治疗实体癌是免疫治疗领域的主要焦点。前列腺癌可能适合基于T细胞的免疫疗法，因为几种肿瘤抗原，包括前列腺干细胞抗原（PSCA），在转移性疾病中广泛过表达。虽然汽车对实体癌的抗原选择性是至关重要的，但由于缺乏真正受限制的肿瘤抗原表达和“中靶脱瘤”活性的潜在安全性问题，这是有问题的。在这里，我们表明细胞内共刺激信号结构域可以决定CAR对肿瘤抗原表达的敏感性。PSCA-CAR中的4-1BB胞内共刺激信号传导结构域与含有CD 28共刺激信号传导结构域的PSCA-CAR相比，赋予了对更高肿瘤抗原密度的改善的选择性、降低的T细胞耗竭表型和等同的肿瘤杀伤能力。PSCA-CAR在患者来源的骨转移性前列腺癌异种移植物模型中表现出稳健的体内抗肿瘤活性，并且与含CD 28的汽车相比，含4- 1BB的汽车显示出上级T细胞持久性和疾病控制。我们的研究证明了共刺激在定义最佳CAR T细胞方面的重要性，并强调了临床相关模型在开发实体癌CAR T细胞疗法中的重要性。
Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.
影响因子：
14.9
作者：
Bates, SE;Zhou, NY;Federico, LE;Xia, L;O'Connor, TR
通讯作者：
O'Connor, TR