Anti-GD3 Chimeric sFv-CD28/T-Cell Receptor ζ Designer T Cells for Treatment of Metastatic Melanoma and Other Neuroectodermal Tumors
Anti-GD3 Chimeric sFv-CD28/T-Cell Receptor ζ Designer T Cells for Treatment of Metastatic Melanoma and Other Neuroectodermal Tumors
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DOI：
10.1158/1078-0432.ccr-10-0043
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发表时间：
2010-05-15
影响因子：
11.5
通讯作者：
Junghans, Richard P.
中科院分区：
文献类型：
--
作者：
Lo, Agnes S. Y.;Ma, Qiangzhong;Junghans, Richard P.
目的：本研究的目的是在体外比较两代GD 3特异性嵌合抗原受体（CAR）在人原代T淋巴细胞中的抗肿瘤活性，并评估使用全身输注白细胞介素-2（IL 2）和设计者T细胞的组合根除裸鼠皮下建立的GD 3（+）黑素瘤的抗肿瘤功效。比较了两代设计T细胞的抗肿瘤活性，第一代祖细胞具有免疫球蛋白T细胞受体（TCR）和信号1，第二代设计T细胞具有信号1+2。渗透性IL-2泵用于提供最大耐受剂量的IL-2，以增强设计师T细胞对皮下建立的黑色素瘤的抗肿瘤作用在nukemi.Results：黑色素瘤与神经节苷脂GD 3的高表达相关，其在抗体治疗中具有适度的效果。我们先前表明，抗GD 3 CAR（sFv-TCR zeta）将募集T细胞以靶向这种非T依赖性抗原，并有效杀死黑色素瘤细胞。在这里，我们报告了添加CD 28共刺激结构域以创建第二代CAR，称为Tandem for two signals。我们发现，这种串联sFv-CD 28/TCR。与没有共刺激的相同CAR相比，T细胞上的CAR受体赋予肿瘤接触时改善的细胞因子分泌、细胞毒性、增殖和克隆扩增的优点。在过继转移模型中，使用建立的黑色素瘤，设计师T细胞与CD 28表现出50%的完全缓解率，但只有在IL 2 supplemented.Conclusions：作为临床开发的试剂，第二代产品显示具有上级属性，以保证其偏好的黑色素瘤和其他肿瘤的临床设计师T细胞免疫治疗。在已建立的肿瘤模型中，需要全身性IL 2以获得最佳活性。临床癌症研究; 16（10）; 2769-80。(C)2010年AACR。
Purpose: The aims of this study are to compare antitumor activities of two generations of GD3-specific chimeric antigen receptors (CAR) in human primary T lymphocytes in vitro and to evaluate the antitumor efficacy of using a combination of systemic infusion of interleukin-2 (IL2) and designer T cells to eradicate subcutaneous established GD3(+) melanoma in nude mice.Experimental Design: Antitumor activities were compared for two generations of designer T cells, the progenitor first-generation with immunoglobulin T-cell receptor (TCR) with Signal 1 and the second-generation designer T cells with Signal 1+2. Osmotic IL2 pumps were used to deliver the maximum tolerated dose of IL2 to enhance the antitumor effects of designer T cells on subcutaneous established melanoma in nude mice.Results: Melanoma is associated with high expression of ganglioside GD3, which has been targeted with modest effect in antibody therapies. We previously showed that an anti-GD3 CAR (sFv-TCR zeta) will recruit T cells to target this non-T-dependent antigen, with potent killing of melanoma cells. Here, we report the addition of a CD28 costimulation domain to create a second-generation CAR, called Tandem for two signals. We show that this Tandem sFv-CD28/TCR. receptor on T cells confers advantages of improved cytokine secretion, cytotoxicity, proliferation, and clonal expansion on tumor contact versus the same CAR without costimulation. In an adoptive transfer model using established melanoma tumors, designer T cells with CD28 showed a 50% rate of complete remissions but only where IL2 was supplemented.Conclusions: As a reagent for clinical development, the second-generation product is shown to have superior properties to warrant its preference for clinical designer T-cell immunotherapy for melanoma and other tumors. Systemic IL2 was required for optimal activity in an established tumor model. Clin Cancer Res; 16(10); 2769-80. (C) 2010 AACR.