【作者】 李丹；

【导师】 聂春来； 王玮；

【作者基本信息】 四川大学 ， 细胞生物学， 2023， 博士

【摘要】 近年来,肿瘤免疫治疗成为继手术、放疗和化疗之后的又一肿瘤治疗手段。作为肿瘤免疫治疗的重要组成部分,嵌合抗原受体(Chimeric antigen receptor,CAR)修饰的T细胞(CAR-T)疗法在恶性血液肿瘤的治疗中展示出良好的临床疗效。上皮细胞黏附分子(Epithelial Cell Adhesion Molecule,EpCAM)在上皮来源的肿瘤中高表达,参与肿瘤的发生发展。同时,EpCAM是肿瘤干细胞(Cancer stem cells,CSCs)和循环肿瘤细胞(Circulating tumor cells,CTCs)的重要生物标志物,与肿瘤的快速进展和转移密切相关。因此,EpCAM是一个理想的肿瘤治疗靶点。虽然部分临床前研究证实EpCAM-CAR-T细胞具有抗肿瘤潜力,但尚缺乏针对该疗法的安全性评估结果支撑其临床应用可行性。同时,作为肿瘤相关抗原(Tumor-associated antigen,TAA),EpCAM在正常上皮组织的低水平表达可能导致脱靶风险。所以,针对EpCAM的CAR-T细胞疗法需要进行系统的安全性评估来探究治疗相关毒性。在这里,我们对EpCAM-CAR-T细胞疗法治疗实体肿瘤的疗效及安全性进行了临床前及临床研究。我们选用一种新型的Dectin-1共刺激信号构建了EpCAM-CAR,并在异种移植瘤模型及EpCAM人源化小鼠模型中证实了EpCAM-CAR-T细胞具有理想的抗肿瘤疗效及良好的安全性。同时,我们开展了以Dectin-1为共刺激信号的EpCAM-CAR-T细胞疗法治疗上皮源性肿瘤的I期临床研究。12例受试者中,6例患者产生了1级或2级毒性事件,1例患者经历了可逆的3级白细胞减少症。此外,没有更严重的毒性事件发生。同时,两例患者在细胞输注后得到部分缓解,3例患者经历了长达23个月的无进展生存。这些临床前及临床研究证实该EpCAM-CAR-T细胞疗法具有良好的安全性及临床应用可行性。更多还原

【Abstract】 Cancer immunotherapy has recently emerged as an adjuvant treatment to surgery,radiotherapy,and chemotherapy.As an important component of cancer immunotherapy,chimeric antigen receptor-modified T cell has shown remarkable success in the treatment of hematological malignancies.The epithelial cell adhesion molecule(EpCAM)has been demonstrated strongly expressed in epithelial tumors.And it is an important biomarker for cancer stem cell(CSC)and circulating tumor cell(CTC)that has been clarified closely associated with tumor metastasis and relapse.Although many studies have validated the antitumor efficacy of EpCAM-CAR-T cells,evidence for the treatment’s safety and clinical feasibility is lacking.EpCAM is a tumor-associated antigen(TAA),and its low expression in normal tissue may induce the risk of on target/off tumor toxicity.To investigate the risk of off-tumor toxicity,it is critical to carefully evaluate the safety of EpCAM-CAR-T cells therapy.In this study,we have evaluated antitumor efficacy and safety of EpCAM-specific CAR-T cells in preclinical and clinical trial.Dectin-1,a novel costimulatory domain,has been integrated into EpCAM-CAR.And Dectin-1 co-stimulated EpCAM-CAR-T cells have shown obvious antitumor activity and acceptable safety in xenograft and EpCAM humanized C57BL/6mice.Meanwhile,we have initiated a phase I clinical trial to investigate the safety and antitumor efficacy of EpCAM-CAR-T cells in patients with advanced epithelial tumors.Six of the twelve enrolled patients have experienced grade 1 or 2 adverse events,one has experienced reversible grade3 leukopenia.Furthermore,two patients achieved partial remission after CAR-T cells infusion,and three have experienced more than 23 months progression-free survival.These findings suggested that EpCAM is an ideal target for cancer immunotherapy and EpCAM-CAR-T cells therapy is a safe and effective treatment for patients with epithelial tumors.更多还原