T cell therapy with L1-CAM-targeting chimeric antigen receptors (CAR) as immune therapy for neuroblastoma patients after haploidentical stem cell transplantation.

使用 L1-CAM 靶向嵌合抗原受体 (CAR) 的 T 细胞疗法作为半相合干细胞移植后神经母细胞瘤患者的免疫疗法。

• 批准号: 213787805
• 负责人: Professorin Dr. Annette Künkele-Langer
• 金额: --
• 依托单位: Jensen Lab
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/213787805?language=en
• 关键词: cell; therapy; L1; CAM; targeting

Adoptive therapy for cancer using genetically retargeted T cells is rapidly emerging as a promising therapeutic modality for hematological malignancies, but significant work remains for effective application to solid tumors. T-depleted haploidentical hematopoietic stem cell transplantation (haploHSCT) represents a versatile platform to facilitate adoptive T cell therapy for patients who have sustained significant damage to their immune systems through prior intensive chemo/radiotherapies, such as children with relapsed neuroblastoma. Currently 90% of children with relapsed neuroblastoma die of disease. Novel therapeutic options are urgently needed for this patient group. Biological parents are haploidentical to their children, and thus, excellent candidates for the source of hematopoietic stem cells and T cells for therapy. We propose that T-depleted haploHSCT, which induces a transient state of profound lymphopenia, is an ideal setting for adoptive transfer of parent-derived central memory T cells genetically modified to express chimeric antigen receptors for targeted recognition of neuroblastoma. Several factors must be optimized for clinical application. Our proposed project has 3 aims: i) to delineate the optimal extracellular domain format and intracellular signaling domain components of a chimeric antigen receptor (CAR) to trigger T cells by human neuroblastoma, ii) to develop genetic systems to regulate the function of CAR-redirected T cells using small molecule transgene expression control technologies and iii) to develop technologies to knock out T cell antigen receptor expression in CAR-modified T cells to eliminate alloreactivity. Safe and effective adoptive therapy has the potential to improve the prognosis for children with recurrent/refractory neuroblastoma. We predict that this project will be informative for several general features of haploHSCT/adoptive therapy for a broad array of additional pediatric solid tumors, to which CARs are being designed.

使用遗传重靶向T细胞的癌症连续治疗正迅速成为血液恶性肿瘤的有希望的治疗方式，但有效应用于实体瘤仍有重要工作要做。T-耗尽的单倍体相合造血干细胞移植（haploHSCT）代表了一种通用平台，以促进通过先前的强化化疗/放疗对其免疫系统持续显著损伤的患者（例如患有复发性神经母细胞瘤的儿童）的过继性T细胞治疗。目前，90%的复发性神经母细胞瘤儿童死于疾病。这一患者群体迫切需要新的治疗选择。生物学上的父母与他们的孩子是单倍性的，因此是造血干细胞和T细胞来源的优秀候选者。我们建议，T-耗尽haploHSCT，诱导一个短暂的状态，深刻的淋巴细胞减少症，是一个理想的设置过继转移的父母来源的中央记忆T细胞的遗传修饰表达嵌合抗原受体的神经母细胞瘤的靶向识别。有几个因素必须优化临床应用。我们的项目有三个目标：i）描绘嵌合抗原受体（CAR）的最佳胞外结构域形式和胞内信号传导结构域组分以通过人神经母细胞瘤触发T细胞，ii）开发遗传系统以使用小分子转基因表达控制技术调节CAR重定向的T细胞的功能，和修饰T细胞以消除同种异体反应性。安全有效的过继治疗有可能改善复发/难治性神经母细胞瘤儿童的预后。我们预测，该项目将为广泛的其他儿科实体瘤的haploHSCT/过继治疗的几个一般特征提供信息，汽车正在设计中。