抗体-配体基序的设计优化以增强 CAR-T 抗实体瘤重定向活性
Design optimization of antibody-ligand motifs to enhance CAR-T redirection activity against solid tumors.
抗原异质性和肿瘤微环境仍是有效CAR-T 细胞疗法的重大障碍,但结合肿瘤内多种抗原及其所处环境的天然配体提供了一种有前景的解决方案。
英文原题:Development and validation of an individualized angiogenesis and tumor-infiltrating lymphocytes prognostic signature in nasopharyngeal carcinoma.
CO V+TIL 评分高的鼻咽癌患者预后更差。
近年来,靶向治疗和免疫治疗已成为晚期、转移性、复发性及耐药性鼻咽癌(NPC)的理想治疗选择,但人们对TIL(肿瘤浸润淋巴细胞)和血管生成因子之间关系及机制认识不足,阻碍了治疗开发和优化。本研究采用免疫组织化学(IHC)检测血管生成相关标志物VEGF-A、VEGFR-2以及TIL(CD4+ T和CD8+ T),并在训练队列(n=124)构建血管生成标志物与TIL共表达的免疫组化评分模型(CO V+TIL评分),再在验证队列(n=114)检验评分系统的准确性和可靠性。研究根据CO V+TIL评分(截断值=28)将训练队列患者分为不同风险组。高危组患者预后较差;其5年总生存期(OS)、无进展生存期(PFS)、局部区域无复发生存期(LRRFS)和无远处转移生存期(DMFS)均低于低危组,且在验证队列中得到确认:高危与低危组的5年OS分别为46.8%和83.4%(HR=3.42,95% CI 1.77–6.61,p<0.001);5年PFS分别为45.9%和81.2%(HR=3.22,95% CI 1.71–6.06,p<0.001);5年LRRFS分别为74.6%和87.5%(HR=3.22,95% CI 1.16–8.93,p=0.027);5年DMFS分别为79.2%和93.2%(HR=2.22,95% CI 0.91–5.39,p=0.086)。多变量分析显示,CO V+TIL评分在训练队列和验证队列中均为独立生存预后指标。将CO V+TIL评分与TNM分期结合可提高生存预测能力。总之,CO V+TIL评分高的NPC患者预后较差。
In recent years, targeted therapy and immunotherapy have become ideal choices for the treatment of advanced, metastatic, recurrent, and drug-resistant nasopharyngeal carcinoma (NPC), but the lack of understanding of the relationship and mechanism between TILs and angiogenic factors hinders therapeutic development and optimization. In this study, the expression of angiogenesis-related markers (VEGF-A,VEGFR-2) and TILs (CD4 + T,CD8 + T) was studied by using immunohistochemistry (IHC). Then we constructed an immunohistochemical scoring model for the co-expression of angiogenesis-related markers and TILs (CO V+TIL score)in the training (n = 124) and validated the accuracy and reliability of the scoring system in the validation cohorts (n = 114), respectively We established the CO V+TIL score model and stratified patients into different risk level in the training cohorts according to CO V+TIL score (cut-off value=28). Patients in the high-risk group had worse prognosis in the training cohorts five-year overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) was lower than that of patients in the low-risk group, and this result was validated in the validation cohorts ( 5-year OS in the high-risk and the low-risk group 46.8% vs. 83.4%, HR: 3.42, 95%CI: 1.77-6.61, p < 0.001); ( 5-year PFS 45.9% vs. 81.2%, HR: 3.22, 95%CI: 1.71-6.06, p < 0.001); ( 5-year LRRFS 74.6% vs. 87.5%, HR: 3.22, 95%CI: 1.16-8.93, p = 0.027); and ( 5-year DMFS79.2% vs. 93.2%, HR: 2.22, 95%CI: 0.91-5.39, p = 0.086). Upon multivariable analysis, CO V+TIL score emerged as an independent prognostic indicator for defining survival in the training cohorts and the validation cohorts. Combining the CO V+TIL score and TNM stage improved the prediction ability of the survival. In conclusion, NPC patients with high CO V+TIL score showed worse prognosis.
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