McNeel Douglas G, Becker Jordan T, Eickhoff Jens C, Johnson Laura E, Bradley Eric, Pohlkamp Isabel, Staab Mary Jane, Liu Glenn, Wilding George, Olson Brian M
Authors' Affiliations: University of Wisconsin Carbone Cancer Center; and
Authors' Affiliations: University of Wisconsin Carbone Cancer Center; and.
Clin Cancer Res. 2014 Jul 15;20(14):3692-704. doi: 10.1158/1078-0432.CCR-14-0169. Epub 2014 May 21.
We have previously reported that a DNA vaccine encoding prostatic acid phosphatase (PAP) could elicit PAP-specific T cells in patients with early recurrent prostate cancer. In the current pilot trial, we sought to evaluate whether prolonged immunization with regular booster immunizations, or "personalized" schedules of immunization determined using real-time immune monitoring, could elicit persistent, antigen-specific T cells, and whether treatment was associated with changes in PSA doubling time (PSA DT).
Sixteen patients with castration-resistant, nonmetastatic prostate cancer received six immunizations at 2-week intervals and then either quarterly (arm 1) or as determined by multiparameter immune monitoring (arm 2).
Patients were on study a median of 16 months; four received 24 vaccinations. Only one event associated with treatment >grade 2 was observed. Six of 16 (38%) remained metastasis-free at 2 years. PAP-specific T cells were elicited in 12 of 16 (75%), predominantly of a Th1 phenotype, which persisted in frequency and phenotype for at least 1 year. IFNγ-secreting T-cell responses measured by ELISPOT were detectable in 5 of 13 individuals at 1 year, and this was not statistically different between study arms. The overall median fold change in PSA DT from pretreatment to posttreatment was 1.6 (range, 0.6-7.0; P = 0.036).
Repetitive immunization with a plasmid DNA vaccine was safe and elicited Th1-biased antigen-specific T cells that persisted over time. Modifications in the immunization schedule based on real-time immune monitoring did not increase the frequency of patients developing effector and memory T-cell responses with this DNA vaccine.
我们之前报道过，一种编码前列腺酸性磷酸酶（PAP）的DNA疫苗能够在早期复发前列腺癌患者中引发PAP特异性T细胞。在当前的试点试验中，我们试图评估通过定期加强免疫进行延长免疫，或使用实时免疫监测确定的“个性化”免疫方案，是否能够引发持久的、抗原特异性T细胞，以及治疗是否与前列腺特异抗原倍增时间（PSA DT）的变化相关。
16例去势抵抗性、非转移性前列腺癌患者每隔2周接受6次免疫接种，随后要么每季度接种一次（第1组），要么根据多参数免疫监测结果进行接种（第2组）。
患者的中位研究时间为16个月；4例接受了24次疫苗接种。仅观察到1例与治疗相关的>2级事件。16例患者中有6例（38%）在2年时无转移。16例患者中有12例（75%）引发了PAP特异性T细胞，主要为Th1表型，其频率和表型至少持续了1年。通过ELISPOT检测，13例个体中有5例在1年时可检测到分泌IFNγ的T细胞反应，且两组之间无统计学差异。从治疗前到治疗后，PSA DT的总体中位变化倍数为1.6（范围为0.6 - 7.0；P = 0.036）。
用质粒DNA疫苗进行重复免疫是安全的，并引发了随时间持续存在的Th1偏向性抗原特异性T细胞。基于实时免疫监测对免疫方案进行调整，并未增加使用这种DNA疫苗产生效应和记忆T细胞反应的患者频率。
