多肽负载DC联合CIK治疗激素难治性前列腺癌的疗效

Efficacy of polypeptide-loaded dendritic cells in combination with cytokine-induced killer cells on hormone refractory prostate cancer

目的:研究多肽负载树突状细胞(dendritic cell,DC)联合细胞因子诱导的杀伤细胞(cytokine-induced killer cell,CIK)对激素难治性前列腺癌(hormone refractory metastatic prostate cancer,HRPC)患者免疫治疗的效果。方法:选择无锡市第四人民医院中西医结合科收治的HLA-A2+HRPC患者26例,分离外周血单个核细胞,其中贴壁细胞经GM-CSF、IL-4联合诱导培养为成熟DC,负载前列腺癌特异性抗原(prostate specific antigen,PSA)、前列腺酸性磷酸酶(prostatic acid phosphatase,PAP)、前列腺特异性膜抗原(prostate specific membrane antigen,PSMA)三个多肽,制备成DC疫苗,经患者腹股沟皮内注射;未贴壁细胞经IFN-γ、IL-2、抗CD3单抗、IL-1体外诱导培养成CIK,经静脉回输给患者。在治疗后1周进行迟发型超敏反应(delayed type hypersensitivity,DTH)检测,在患者治疗前后进行血清中细胞因子和PSA检测,治疗结束后4周进行短期疗效评价。结果:26例HRPC患者对DC联合CIK治疗的耐受良好。治疗后患者血清中IL-2、IL-12、IFN-γ水平较治疗前显著升高(上升幅度分别为65.07%、67.69%和125.38%,P<0.05或P<0.01),TNF-α和IL-10水平变化不大;DTH的阳性率为43.5%(10/23);7例患者的CD8+IFN-γ+T细胞比例较治疗前显著提高[(8.95±2.74)%vs(0.39±0.15)%,P<0.01];8/26例患者的PSA下降,降幅为13%～66%。26例患者短期疗效评价,3例PR、4例PD、19例SD,所有患者治疗中未出现明显不良反应。结论:多肽负载DC联合CIK治疗HRPC能激发患者的免疫应答、诱导Th1型细胞因子的分泌,近期疗效良好,是一种安全的治疗方法。

Objective： To investigate the efficacy of polypeptide-loaded dendritic cells （DCs） in combination with cytokine-induced killer cells （CIKs） against hormone refractory metastatic prostate cancer （ HRPC ） patients. Methods ： Twenty-six HLA-A2 ＋ patients with HRPC were enrolled from the Department of Chinese Traditional and Western Medicine of the Wuxi No. 4 People＇ s Hospital. Peripheral blood mononuclear cells （PBMCs） were separated, and the adherent cells were induced into DCs by GM-CSF and IL-4. Then DCs were loaded with three peptides （prostate specific antigen, PSA; prostatic acid phosphatase, PAP; prostate specific membrane antigen, PSMA） to prepare DC vaccine and were injected intracutaneously. The un-adherent cells of PBMCs were induced into CIK by IFN-γ, IL-2, CD3 monoclonal antibody and IL-1, and were injected intravenously. Delayed type hypersensitivity （DTH） was detected one week after treat- ment, and cytokine and PSA in serum were determined before and after treatment. The short-term efficacy was evaluated 4 weeks after treatment. Results： DC-CIK therapy was well tolerated in 26 HRPC patients. The serum IL-2, IL-12, and IFN-γ levels after therapy were significantly increased （ increased 65.07% , 67.69% and 125.38% , P 〈 0.05 or P 〈0. 01 ） , while TNF-α and IL-10 levels were unchanged. The positive rate of DTH was 43.5% （10/23）. The proportion of CD8 ^＋ IFNγ^ ＋ cells after therapy was significantly increased （ [ 8.95 ± 2.74 ] % vs [ 0.39 ± 0. 151%, P 〈 0.01 ）. A decrease of PSA （13% to 66% ） was observed in 8 of 26 patients. The short-term efficacy of 26 HRPC patients was evaluated, with 3 PR, 4 PD, and 19 SD after treatment, and no severe adverse reaction was observed. Conclusion： The polypeptide-loaded DC in combination with CIK therapy can elicit specific immune responses in HRPC patients, and induce type I eytokine secretion with well short-term clinical efficacy, indicating that DC-CIK therapy is a safe treatment for HRPC.