Perales-Puchalt Alfredo, Svoronos Nikolaos, Rutkowski Melanie R, Allegrezza Michael J, Tesone Amelia J, Payne Kyle K, Wickramasinghe Jayamanna, Nguyen Jenny M, O'Brien Shane W, Gumireddy Kiranmai, Huang Qihong, Cadungog Mark G, Connolly Denise C, Tchou Julia, Curiel Tyler J, Conejo-Garcia Jose R
Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania.
Clin Cancer Res. 2017 Jan 15;23(2):441-453. doi: 10.1158/1078-0432.CCR-16-0492. Epub 2016 Jul 19.
To define the safety and effectiveness of T cells redirected against follicle-stimulating hormone receptor (FSHR)-expressing ovarian cancer cells.
FSHR expression was determined by Western blotting, immunohistochemistry, and qPCR in 77 human ovarian cancer specimens from 6 different histologic subtypes and 20 human healthy tissues. The effectiveness of human T cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T cells.
FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. Accordingly, T cells expressing full-length FSHR-redirected chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T cells persisted as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor-transduced T cells away from targeted tumor cells.
T cells redirected against FSHR tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries. Clin Cancer Res; 23(2); 441-53. ©2016 AACR.
确定重定向针对表达促卵泡激素受体（FSHR）的卵巢癌细胞的T细胞的安全性和有效性。
通过蛋白质免疫印迹法、免疫组织化学和定量聚合酶链反应（qPCR）检测了来自6种不同组织学亚型的77例人卵巢癌标本和20例人健康组织中的FSHR表达情况。使用针对患者来源异种移植瘤的一组样本，测定了体内用全长FSH靶向的人T细胞的有效性。使用靶向小鼠FSHR的构建体和同基因T细胞，在具有免疫活性的荷瘤小鼠中证实了安全性和有效性。
FSHR在不同组织学类型的妇科恶性肿瘤中表达，但在非卵巢健康组织中不表达。因此，表达全长FSHR重定向嵌合受体的T细胞在体内对一组患者来源的肿瘤介导了显著的治疗效果（包括肿瘤排斥）。在生长同基因、原位和侵袭性卵巢肿瘤的具有免疫活性的小鼠中，完全靶向小鼠FSHR的T细胞也提高了生存率，且没有任何可测量的毒性。值得注意的是，嵌合受体增强了内源性肿瘤反应性T细胞在过继转移至随后受到相同肿瘤攻击的幼稚受体后消除恶性进展的能力。有趣的是，在疾病末期，靶向FSHR的T细胞作为记忆淋巴细胞持续存在，在没有肿瘤细胞免疫编辑的情况下，没有明显的程序性死亡蛋白1（PD-1）依赖性耗竭。然而，晚期肿瘤腹水中的外泌体将这种以及其他嵌合受体转导的T细胞的效应活性从靶向肿瘤细胞转移开。
用全长FSH重定向针对FSHR肿瘤细胞的T细胞代表了一种针对广泛卵巢恶性肿瘤的有前景的治疗选择，即使在无肿瘤卵巢中存在同源靶点的情况下，其毒性也可忽略不计。《临床癌症研究》；23(2)；441 - 53。©2016美国癌症研究协会。
