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嵌合抗原受体修饰的T细胞(CAR-T)在浆膜腔内的抗肿瘤效应及其机制

批准号81673001 学科分类肿瘤生物治疗 ( H1611 )
项目负责人王永生 负责人职称教授 依托单位四川大学
资助金额59.00
万元
项目类别面上项目 研究期限2017 年 01 月 01 日 至
2020 年 12 月 31 日
中文主题词嵌合抗原受体修饰T细胞(CAR-T);浆膜腔癌转移;C24_卵巢肿瘤;C05_气管、支气管、肺肿瘤;C08_结、直肠肿瘤
英文主题词Chimeric antigen receptor-modified T cell (CAR-T);Cancer metastases in serous cavity;Ovarian Cancer;Lung cancer;Colorectal cancer

摘要

中文摘要 嵌合抗原受体修饰T细胞(CAR-T)具有抗原依赖的强大杀肿瘤活性。肿瘤浆膜腔转移伴恶性积液临床疗效差、危害大。癌细胞在浆膜腔易于上皮间质转化并产生更多肿瘤干细胞,发生抗原调变,同时癌细胞和免疫细胞PD-L1上调,促进免疫逃逸。本项目致力于浆膜腔转移的CAR-T局部治疗,拟监测癌细胞浆膜腔暴露后CAR-T靶向抗原的变化,已在前期证实VEGFR1在腹水癌细胞及腹水处理细胞系稳定表达。本项目设计了双靶向VEGFR1和PD-L1的拼接信号CAR,将PD-L1抑制转化为激活信号4-1BB,增强CAR-T的杀伤和存活。项目前期还发现IL-2有助增强CAR-T在腹水环境下的杀伤活性。在前期基础上,本项目拟研究CAR-T,特别是双靶向CAR-T对肿瘤浆膜腔转移的预防和治疗作用,验证免疫效应的分子机制,优化CAR-T治疗策略。项目有望推动CAR-T在实体瘤中的临床应用,为浆膜腔癌转移提供有效预防和治疗手段。
英文摘要 Chimeric antigen receptor-modified T cells (CAR-T) have powerful killing activity for tumor cells in an antigen dependent manner. Tumor metastases in serous cavity frequently occurs in patients with lung cancer, ovarian cancer, and so on, accompanying with severe clinical symptom and worse prognosis. Cancer cells are prone to initiate epithelial–mesenchymal transition (EMT) and generate more cancer stem cells in serous cavity, modulate antigens expression. Moreover, both cancer and monocytes also unregulated the level of PD-L1 expression. These changes can induce immune escape. The project aims to regional immunotherapy using CAR-T for cancer metastases in serous cavity. We will monitor the modulation of surface targeting antigen profile of CAR-T therapy on cancer cells when exposed in serosa cavity. Previously, we found that VEGFR1 expressed on cancer cells from malignant ascites and malignant ascites treated cancer cell lines. Therefore, we developed a split signal CAR to target VEGFR1 and PD-L1, trying to switch inhibitory signal of PD-L1 to activating signal, 4-1BB, for promoting CAR-T killing and survival. We also found that IL-2 enhanced killing activity within malignant ascites. Based on our previous studies, we are going to further investigate the effects on prevention and treatment for cancer metastases in serous cavity, confirm the immune mechanism, and optimize the therapeutic strategy. The project will be helpful to promote clinical application through providing an effective war to prevent and treat cancer metastases in serous cavity.
结题摘要

成果

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