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目的:评价自体热休克凋亡肿瘤细胞抗原负载DC对Ⅰ到Ⅳ期ER、PR、Her2三阴性乳腺癌(triple-negative breast cancer,TNBC)患者治疗的疗效和患者对该治疗的耐受性。方法:入选南京、常州、无锡三地3个医院的TNBC患者168例,按照2∶1的比例使用随机数字表将患者随机分组为DC免疫组112例、对照组56例。DC疫苗治疗每周1次,4次为1个疗程,疗程间间隔1个月,共3个疗程。疫苗治疗前、后检测患者外周血中细胞因子谱(IL-2、IL-10、IL-12、TNF-α和IFN-γ)水平和肿瘤特异性CD8+IFNγ+T细胞比例以及进行DTH试验。末次治疗后每3个月随访1次,随访2年,统计患者疾病无进展生存率(PFSR)。结果:Ⅰ~Ⅲ期TNBC患者DC免疫治疗1个疗程后,IL-2、TNF-α和IFN-γ水平即较治疗前(基线)显著升高(P IL-2=0.038 4、P TNF-α=0.023 7、P IFN-γ=0.022 1),且随疗程增加其水平不断升高;而Ⅳ期TNBC患者治疗3个疗程后细胞因子水平均无明显提高。Ⅰ~Ⅲ期TNBC患者外周血CD8+IFN-γ+T细胞比例提升速度与幅度较为缓慢,3个疗程后提升幅度才显示有统计学意义(P<0.05)。患者的DTH试验阳性率伴随疗程数的增加而提升,两者呈正相关关系(r=0.973);早期(Ⅰ期和Ⅱ期)TNBC患者DTH平均阳性率明显高于中晚期患者(Ⅲ期和Ⅳ期)。2年随访期内Ⅰ~Ⅱ期TNBC患者病情均较稳定,生存率100%;Ⅲ~Ⅳ期TNBC患者DC治疗组PFSR明显高于对照组(71.43%vs 32.73%,P<0.05)。Ⅰ~Ⅳ期DTH阳性患者的PFSR明显高于DTH阴性患者(87.30%vs 51.02%,P<0.05)。治疗组112例TNBC患者对DC治疗耐受良好,未发现Ⅱ级以上不良反应。结论:自体热休克凋亡肿瘤细胞抗原负载DC可有效诱导早期TNBC患者产生Th1型免疫应答反应,分泌高水平Th1型抗瘤因子,3个疗程后可激发明显的肿瘤抗原特异性CTL反应,DTH试验可作为DC免疫有效性的评价指标之一。该DC免疫治疗方法可抑制晚期TNBC患者疾病进展,从而提高PFSR,患者耐受性良好。
OBJECTIVE: To evaluate the efficacy of autologous heat-shocked tumor cell antigen-loaded DC in the treatment of patients with stage Ⅰ-Ⅳ ER, PR, Her2 triple-negative breast cancer (TNBC) and their tolerance to the treatment. Methods: A total of 168 TNBC patients were enrolled in 3 hospitals in Nanjing, Changzhou and Wuxi. According to a 2: 1 ratio, patients were randomly divided into 112 cases of DC and 56 cases of control. DC vaccine treatment once a week, 4 times for a course of treatment, treatment interval of 1 month, a total of 3 courses. The levels of cytokines (IL-2, IL-10, IL-12, TNF-α and IFN-γ) and tumor-specific CD8 + IFNγ + T cells in the peripheral blood of the patients before and after the vaccine treatment were tested, and the DTH test . The patients were followed up every 3 months after the last treatment and followed up for 2 years. The PFSR was calculated. Results: The levels of IL-2, TNF-α and IFN-γ in patients with stage Ⅰ-Ⅲ TNBC after one course of immunotherapy were significantly higher than those before treatment (P IL-2 = 0.038 4, P TNF- α = 0.023 7, P IFN-γ = 0.022 1), and its level increased with the course of treatment. However, the level of cytokines in stage Ⅳ TNBC patients did not significantly increase after 3 courses of treatment. The proportion of CD8 + IFN-γ + T cells in peripheral blood of stage Ⅰ ~ Ⅲ patients increased slowly and slowly, and the increase extent after 3 courses showed statistical significance (P <0.05). The positive rate of DTH in patients with TNBC increased with the increase of the number of courses, and there was a positive correlation between them (r = 0.973). The average positive rate of DTH in early stage (stage Ⅰ and stage Ⅱ) TNBC patients was significantly higher than that in advanced stage (stage Ⅲ and Ⅳ period). The TNBC patients with Stage Ⅰ ~ Ⅱ status were stable at 2 years of follow-up, with a 100% survival rate. PFSR in DCBC patients in stage Ⅲ ~ Ⅳ was significantly higher than that in control group (71.43% vs 32.73%, P <0.05). The PFSR of stage Ⅰ ~ Ⅳ DTH positive patients was significantly higher than that of negative DTH patients (87.30% vs 51.02%, P <0.05). One hundred and twelve TNBC patients in the treatment group were well tolerated with DC and no grade Ⅱ or higher adverse reactions were found. CONCLUSIONS: Autologous heat-shocked apoptotic tumor cell antigen-loaded DCs can effectively induce Th1-type immune response in early-stage TNBC patients and secrete high-level Th1-type anti-tumor factors. After 3 courses of treatment, significant tumor antigen-specific CTL responses can be induced. Test can be used as an indicator of the effectiveness of DC immunization. This DC immunotherapy method can inhibit disease progression in patients with advanced TNBC, thereby increasing PFSR, patients with good tolerance.