人表皮生长因子受体2多肽负载自体树突状细胞治疗乳腺癌的疗效分析

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ⅠIII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ⅢⅡ期患者DTH平均阳性率明显高于Ⅲ^Ⅳ期患者(P<0.05)。ⅠⅣ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%;ⅢⅡ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IIIIV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。

A study of the effect of autologous dendritic cells pulsed with HER-2 peptides to immunity of 164 breast cancer patients

Objective To study the effect of autologous dendritic cells pulsed with HER-2 peptides to immune tolerance and immune responses of 164 breast cancer patients.Methods 246 breast cancer patients were selected,including 164 DC vaccination patients and 82 controls.Three cycles of DC vaccines were administered,four weekly injections as one cycle,followed by next cycle with one month interval.The possible side effects and the tolerance to DC vaccination were observed.The non-specific and tumor specific immune responses including cytokine profiles（IL-2,IL-10,IL-12,TNF-α and IFN-γ） and the percentage of specific CD＋8,IFN-γ＋and T lymphocytes in peripheral blood as well as the delayed type IV hypersensitivity reaction（DTH） were all tested before and after DC vaccinations.DPT and PFSR were calculated after 2year follow up.Results No more than level II side effects were found in all participants.After one cycle of vaccines,Th1 type of cytokine levels of stage I to stage III patients including IL-2 and IFN-γ increased significantly（PIL-2= 0.0472,PIFN-γ= 0.0153） and maintained in higher level for a long period.Tumor specific CD＋8,IFN-γ＋and T lymphocytes were induced and activated.The numbers of CD＋8,IFN-γ＋and T showed apparent expansions after the third cycle of DC vaccines.DTH positive rate increased along with the vaccination cycles,showing a positive correlation with r = 0.997.But,DTH positive rate in stage I to stage II patients were found clearly higher than that of stage III to stage IV patients.The average DPT were respectively689 and 667 days of stage III and stage IV patients with DC vaccinations,614 and 573 days in corresponding controls.The average PFSR of stage III and stage IV patients was 75.9%,but only 54.6% for controls（P = 0.0048）.Furthermore,the average PFSR of DTH positive patients were 78.6%,much higher than that of DTH negative patients（67.0%,P = 0.0189）.Conclusions Autologous dendritic cells pulsed with HER-2 peptides are effective in eliciting both Th1 type of non-s