T cells redirected to interleukin-13Rα2 with interleukin-13 mutein--chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1.
T cells redirected to interleukin-13Rα2 with interleukin-13 mutein--chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1.
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DOI：
10.1016/j.jcyt.2014.02.012
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发表时间：
2014-08
期刊：
影响因子：
4.5
通讯作者：
Gottschalk, Stephen
中科院分区：
文献类型：
--
作者：
Krebs, Simone;Chow, Kevin K. H.;Yi, Zhongzhen;Rodriguez-Cruz, Tania;Hegde, Meenakshi;Gerken, Claudia;Ahmed, Nabil;Gottschalk, Stephen
尽管积极的多模式治疗，胶质母细胞瘤患者的预后仍然很差。靶向IL13R的表达嵌合抗原受体（CARs）的基因修饰T细胞的免疫治疗[j]。α]2, HER2， EGFRvIII或EphA2在临床前模型中显示出治疗胶质瘤的希望。基于IL13Rα2靶向免疫毒素，研究人员构建了以IL13Rα2为抗原结合域的car，这些免疫毒素含有含有一个或两个氨基酸取代的IL13分子（IL13 muteins），以赋予IL13Rα2特异性。虽然免疫毒素背景下IL13突变蛋白的特异性已被很好地表征，但CAR - T细胞的信息有限。我们构建了四个含有IL13突变蛋白的第二代car，这些突变蛋白被替换了一个或两个氨基酸。通过IFNα的产生判断，表达所有四种car的T细胞识别IL13Rα1或IL13Rα2重组蛋白，而不是对照蛋白（IL4R）。IL13Rα2蛋白诱导的IL2明显增加，表明IL13突变蛋白car - T细胞对IL13Rα2的亲和力高于IL13Rα1。在细胞毒性试验中，与IL13Rα1-和il13r α2阴性对照相比，CAR - T细胞杀死了IL13Rα1-和/或il13r α2阳性细胞。虽然我们在体外没有观察到IL13 mutein CAR - T细胞之间的显著差异，但只有表达带有E13K氨基酸替代的IL13 mutein CAR的T细胞在体内具有抗肿瘤活性，从而导致治疗动物的生存优势。我们的研究强调了配体的特异性/亲切性是依赖于环境的，并且在临床前动物模型中评估CAR - T细胞对于评估其潜在益处至关重要。
Outcomes for patients with glioblastoma remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting IL13R[.alpha]2, HER2, EGFRvIII, or EphA2 has shown promise for the treatment of glioma in preclinical models. Based on IL13Rα2-targeted immunotoxins that contain IL13 molecules with one or two amino acid substitutions (IL13 muteins) to confer specificity to IL13Rα2, investigators have constructed CARs with IL13 muteins as antigen binding domains. While the specificity of IL13 muteins in the context of immunotoxins is well characterized, limited information is available for CAR T cells. We constructed four 2nd generation CARs with IL13 muteins with one or two amino acid substitutions. T cells expressing all four CARs recognized IL13Rα1 or IL13Rα2 recombinant protein in contrast to control protein (IL4R) as judged by IFNα production. IL13Rα2 protein induced significantly more IL2, indicating that IL13 mutein-CAR T cells have a higher affinity to IL13Rα2 than IL13Rα1. In cytotoxcity assays, CAR T cells killed IL13Rα1- and/or IL13Rα2-positive cells in contrast to IL13Rα1- and IL13Rα2-negative controls. While we observed no significant differences between IL13 mutein CAR T cells in vitro, only T cells expressing IL13 mutein CARs with an E13K amino acid substitution had antitumor activity in vivo that resulted in a survival advantage of treated animals. Our study highlights that the specificity/avidity of ligands is context-dependent and that evaluating CAR T cells in preclinical animal model is critical to assess their potential benefit.
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影响因子：
4.8
作者：
Madhankumar, AB;Mintz, A;Debinski, W
通讯作者：
Debinski, W
影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M
影响因子：
20.3
作者：
Gottschalk, S;Edwards, OL;Rooney, CM
通讯作者：
Rooney, CM
带有嵌合抗原受体的T细胞具有有效的抗肿瘤作用，可以在晚期白血病患者中建立记忆。
影响因子：
17.1
作者：
Kalos M;Levine BL;Porter DL;Katz S;Grupp SA;Bagg A;June CH
通讯作者：
June CH
DOI：
10.1158/1078-0432.ccr-09-1322
发表时间：
2010-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ahmed N;Salsman VS;Kew Y;Shaffer D;Powell S;Zhang YJ;Grossman RG;Heslop HE;Gottschalk S
通讯作者：
Gottschalk S