A Novel Chimeric Antigen Receptor Against Prostate Stem Cell Antigen Mediates Tumor Destruction in a Humanized Mouse Model of Pancreatic Cancer
A Novel Chimeric Antigen Receptor Against Prostate Stem Cell Antigen Mediates Tumor Destruction in a Humanized Mouse Model of Pancreatic Cancer
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DOI：
10.1089/hum.2013.209
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发表时间：
2014-12-01
影响因子：
4.2
通讯作者：
Morgan, Richard A.
中科院分区：
文献类型：
--
作者：
Abate-Daga, Daniel;Lagisetty, Kiran H.;Morgan, Richard A.
尽管对胰腺癌分子病理生理学的理解取得了进展，但胰腺癌在很大程度上仍然无法治愈，这突出了对新型疗法的需求。我们开发了一种特异于前列腺干细胞抗原（PSCA）的嵌合抗原受体（CAR），PSCA是一种在胰腺癌恶性转化早期开始过度表达的糖蛋白。为了优化CAR设计，我们使用了来自小鼠或人抗体的抗原识别结构域，以及除了CD 3 ζ之外还含有一个或两个T细胞共刺激元件的细胞内信号传导结构域。比较多个构建体确定了基于人单克隆抗体Ha 1 -4.117的CAR在体外具有最大的反应性。为了进一步分析这种CAR，我们开发了一种人胰腺癌异种移植模型，并将CAR工程化T细胞过继转移到具有已建立肿瘤的动物中。CAR工程化的人淋巴细胞诱导了显著的抗肿瘤活性，与其他汽车不同，第二代CAR（含有CD 28共信号结构域）诱导的抗肿瘤作用比第三代CAR（含有CD 28和41 BB共信号结构域）更强。虽然我们的研究结果提供了支持PSCA作为胰腺癌基于CAR的免疫疗法的靶抗原的证据，但PSCA在选定的正常组织上的表达可能是限制毒性的来源。
Despite advances in the understanding of its molecular pathophysiology, pancreatic cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate stem cell antigen (PSCA), a glycoprotein that is overexpressed in pancreatic cancer starting at early stages of malignant transformation. To optimize the CAR design, we used antigen-recognition domains derived from mouse or human antibodies, and intracellular signaling domains containing one or two T cell costimulatory elements, in addition to CD3zeta. Comparing multiple constructs established that the CAR based on human monoclonal antibody Ha1-4.117 had the greatest reactivity in vitro. To further analyze this CAR, we developed a human pancreatic cancer xenograft model and adoptively transferred CAR-engineered T cells into animals with established tumors. CAR-engineered human lymphocytes induced significant antitumor activity, and unlike what has been described for other CARs, a second-generation CAR (containing CD28 cosignaling domain) induced a more potent antitumor effect than a third-generation CAR (containing CD28 and 41BB cosignaling domains). While our results provide evidence to support PSCA as a target antigen for CAR-based immunotherapy of pancreatic cancer, the expression of PSCA on selected normal tissues could be a source of limiting toxicity.