自体性嵌合体抗原受体基因修饰的T细胞靶向性治疗IL-11Ra过表达的恶性肿瘤

Despite great progress in cancer therapy by the combination of surgery, chemotherapy and radiation, most patients with cancers remain incurable and the prognosis of patients with developed disease is poor. The use of genetically modified T-cells with tumor-specific chimeric antigen receptors (CARs) has been emerged as a novel treatment of cancer. CARs are fusion proteins between an extracellular domain recognizing tumor associated antigens and intracellular signaling domains such as CD3ζ chain. Antigen-recognition redirects CAR-T cells to tumor cells and initiates T-cell activation. CD19 specific CAR-T cells have successfully eliminated leukemia cells in 3 patients..CAR-T cells have several advantages over other immunotherapies. Unlike native antibodies, CAR-T cells can actively migrate to tumor sites led by chemokine gradients and enhance anti-tumor effects by recruiting multiple cytotoxic mechanisms. Compared to native T cell receptor modified T cells, CAR-T cells recognizing tumor antigens is HLA independent and thus can overcome the ability of tumor escaping immune surveillance by downregulation of HLA. Moreover, CAR-T cells with co-stimulator motifs in the CAR resist the suppressive effects of Treg cells in the tumor microenvironment. Furthermore, multiple subset (CD4, CD8, na?ve and memory) CAR-T cells can improve the anti-tumor effect overall..The tumor antigen is a critical determinant for the CAR-T cell therapy.IL-11Rα is overexpressed in many cancers and can function as a therapeutic target of prostate cancer and osteosarcoma(OS). We have demonstrated that IL-11Rα specific CAR-T cells can kill OS cells and result in regression of the lung metastases. Further investigations in this proposal are necessary to promote the application of CAR-T cells to treat the patients:.1. Two 3rd-generation CARs targeting IL-11Ra constructed in a non-viral Sleeping Beauty transporson vector will be used to generate CAR-T cells and their anti-tumor effects will be evaluated. 2. Patient's own T cells have been used to produce autologous CAR-T cells to avoid graft-versus-host disease in the clinical setting. Therefore, the anti-tumor effect of autologous CAR-T cells targeting the tumor cells derived from same patients will be evaluated. 3. In the solid tumors, the effect of CAR-T cells is dependent on the capability of CAR-T cells homing to the tumor sites and targeting tumor cells by specific antigen-recognition. By using two complementary portions of luciferase fused to CAR and tumor antigen, respectively, we will evaluate the homing and direct targeting of CAR-T cells by imaging assay..4. The exclusive tumor specific antigen is rare available in reality. IL-11Rα has limited expression in megakaryocytes and gastrointestinal tissues. Therefore, we will investigate the strategies to avoid or minimize the undesirable CAR-T cells related "on target/off tumor" toxicity by optimizing the number, frequency and route of the CAR-T cells infused in vivo.

嵌合体抗原受体基因修饰的T细胞（CAR-T细胞）能特异性地识别肿瘤抗原并杀灭肿瘤细胞，已在近来的靶向免疫治疗肿瘤中取得了显著的成效。IL-11Rα在骨肉瘤和前列腺癌中过表达；在我们的前期工作中，以IL-11Rα为靶向的CAR（IL-11Rα-CAR）T细胞，能有效地杀灭骨肉瘤细胞并引起动物肺转移瘤的退缩。然而，实验工作中异体源性CAR-T细胞对肿瘤细胞的效应结果，常不能最准确地反映临床中为避免移植物抗宿主反应而采用的自体性CAR-T细胞的杀瘤效应。为了给IL-11Rα-CAR T细胞应用于临床治疗骨肉瘤和前列腺癌提供更为可靠的实验依据，我们拟制备自体性IL-11Rα-CAR T细胞，并研究其对同一患者肿瘤靶向和杀伤效应。同时，应用非病毒性并有稳定高效表达能力的转座子载体构建具高效杀瘤效应的第三代CAR-T细胞，并探索其在动物体内的导向，直接靶向作用和杀瘤效果。

1) 嵌合抗原受体修饰T细胞（CAR-T细胞）治疗是近年来发展迅猛的肿瘤免疫治疗新进展。针对CD19的CAR-T细胞在治疗复发难治的B细胞性血液肿瘤中取得了显著疗效。但是，CAR-T细胞在治疗实体性恶性肿瘤中效果尚欠佳。本项目主要为探索CAR-T细胞治疗恶性实体瘤进行研究。a）设计新型CAR-T细胞用于克服实体性肿瘤的免疫抑制性微环境。在以EGFRviii为靶向的CAR-T细胞治疗恶性胶质瘤中，通过PD-1-CD28嵌合分子将PD-1介导的抑制性信号转换为CD28介导的活化信号。共表达PD-1-CD28的EGFRviii-CAR-T细胞，可提高CAR-T细胞对肿瘤的杀伤和抑制肿瘤的复发。另一方面，通过GPC3-CAR-T细胞进行肝癌的治疗研究，GPC3-CAR-T细胞能有效杀伤肝癌细胞并抑制肿瘤生长。2）野生型EGFR在肿瘤生长中具有酪氨酸激酶非依赖性的功能，有别于传统认为的EGFR酪氨酸激酶的活性功能。降解EGFR蛋白，而非抑制EGFR酪氨酸激酶活性，能够通过诱导肿瘤细胞的线粒体自噬引起凋亡并抑制小鼠模型中的肿瘤生长。靶向EGFR酪氨酸激酶非依赖性功能有可能用于发展治疗过表达野生型EGFR的肿瘤以及酪氨酸激酶抑制剂的肿瘤。

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