论文部分内容阅读
目的探讨人表皮生长因子受体2(HER-2)多肽负载自体树突状细胞对乳腺癌患者免疫耐受性、免疫应答水平的影响和临床疗效。方法选取HLA-A201阳性和HER-2阳性乳腺癌患者246例,其中观察组164例,对照组82例,两组患者均给予化疗或内分泌治疗。其中观察组患者给予树突状细胞(DC)免疫治疗每周1次,4次为1个疗程,连续3个疗程,疗程间隔时间为1个月;对照组未给予DC免疫治疗。于免疫治疗前后监测患者外周血中IL-2、IL-10、IL-12、TNF-α和IFN-γ水平,肿瘤特异性CD+8、IFNγ+和T淋巴细胞比例和迟发型超敏反应(delayed type hypersensitivity,DTH)试验。末次免疫后每3个月随访1次,随访2年后统计患者疾病进展时间(TTP)和无进展生存率(PFS)。结果观察组患者对DC疫苗均耐受良好,未发现II级以上不良反应发生。I~III期患者DC免疫治疗1个疗程后IL-2和IFN-γ总体水平均较治疗前(基线)显著升高(P<0.05),并维持较长时间的高水平状态;而IV期患者3个疗程完成后细胞因子水平仍无明显提高。3个疗程后外周血中特异性CD+8、IFN-γ+和T细胞得到明显扩增。DTH阳性率与免疫次数亦呈正相关关系(r=0.997),并且Ⅰ~Ⅱ期患者DTH平均阳性率明显高于Ⅲ~Ⅳ期患者(P<0.05)。Ⅰ~Ⅱ期患者2年随访期内病情均较稳定,生存率为100%;Ⅲ~IV期患者平均TTP为689d和667d,而对照组分别为614d和573d,分别延长了75d和94d,差异有统计学意义(P<0.05)。观察组III~IV期患者平均PFS为75.9%,而同期对照组仅为54.6%,差异有统计学意义(P<0.05)。DTH阳性患者(70例)平均PFS为78.6%,而DTH阴性患者(94例)平均PFSR为67.0%,差异有统计学意义(P<0.05)。结论负载HER-2多肽的自体DC可有效诱导早、中期HER-2阳性乳腺癌患者产生TH1型免疫应答反应,分泌可持续高水平的Th1型抗瘤因子,多疗程后可激发明显的肿瘤抗原特异性CTL反应,并可抑制晚期患者疾病进展,提高无进展生存率与生存质量,可作为HER-2阳性患者安全、有效的辅助治疗手段。
Objective To investigate the effect of human epidermal growth factor receptor 2 (HER-2) polypeptide loaded with autologous dendritic cells on immune tolerance and immune response in patients with breast cancer and its clinical efficacy. Methods A total of 246 patients with HLA-A201-positive and HER-2 positive breast cancer were selected, including 164 in the observation group and 82 in the control group. Both groups were given chemotherapy or endocrine therapy. The patients in the observation group received dendritic cell (DC) immunotherapy once a week, 4 times for one course of treatment for 3 consecutive courses of treatment for one month; the control group was not given DC immunotherapy. The levels of IL-2, IL-10, IL-12, TNF-α and IFN-γ in peripheral blood of patients before and after immunotherapy were monitored. The proportion of tumor-specific CD + 8, IFNγ + and T lymphocytes and delayed-type hypersensitivity (delayed type hypersensitivity, DTH) test. The patients were followed up every 3 months after the last immunization and the patients’ disease progression time (TTP) and progression-free survival (PFS) were counted after 2 years of follow-up. Results The patients in the observation group were well tolerated with DC vaccine and no adverse reactions of grade II or higher were found. The levels of IL-2 and IFN-γ in patients with stage I to III DC immunotherapy were significantly higher than those before treatment (baseline) (P <0.05), and maintained for a long time to a high level. In stage IV The level of cytokines remained unchanged after 3 courses of treatment were completed. After 3 courses of treatment, the specific CD + 8, IFN-γ + and T cells in peripheral blood were significantly increased. The positive rate of DTH was positively correlated with the number of immunizations (r = 0.997), and the average positive rate of DTH in stage Ⅰ ~ Ⅱ patients was significantly higher than that in stage Ⅲ ~ Ⅳ patients (P <0.05). The patients in stage Ⅰ ~ Ⅱ were stable in 2 years follow-up with a survival rate of 100%. The mean TTP in stage Ⅲ ~ IV was 689 days and 667 days, while the control group was 614 days and 573 days respectively, which were prolonged 75 days and 94 days, respectively There was statistical significance (P <0.05). The average PFS in observation group III-IV patients was 75.9%, compared with 54.6% in the control group at the same period, the difference was statistically significant (P <0.05). The average PFS was 78.6% in DTH-positive patients (70 cases), and 67.0% in DTH-negative patients (94 cases), the difference was statistically significant (P <0.05). Conclusion Autologous DCs loaded with HER-2 polypeptide can effectively induce TH1-type immune response in early-stage and mid-term HER-2 positive breast cancer patients and secrete high-level Th1 anti-tumor factor in a sustained manner. After multiple courses of treatment, significant tumor antigens can be induced Specific CTL response and can inhibit the progression of disease in patients with advanced disease and improve the progression-free survival rate and quality of life, and can be used as a safe and effective adjuvant therapy for HER-2-positive patients.