DNA vaccine encoding prostatic acid phosphatase (PAP) elicits long-term T-cell responses in patients with recurrent prostate cancer.
DNA vaccine encoding prostatic acid phosphatase (PAP) elicits long-term T-cell responses in patients with recurrent prostate cancer.
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DOI：
10.1097/cji.0b013e3181dda23e
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发表时间：
2010-07
期刊：
影响因子：
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通讯作者：
McNeel DG
中科院分区：
文献类型：
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作者：
Becker JT;Olson BM;Johnson LE;Davies JG;Dunphy EJ;McNeel DG
前列腺酸性磷酸酶（PAP）是前列腺癌中的肿瘤抗原，也是早期临床试验中几种抗肿瘤疫苗的靶点。最终，抗肿瘤疫苗的目标是引发可持续的免疫反应，能够根除肿瘤，或至少抑制其生长。我们已经研究了质粒DNA疫苗，并且先前已经进行了1期试验，其中复发性前列腺癌患者接种编码PAP的DNA疫苗。在这项研究中，我们调查了后续加强免疫的免疫效果，并进行了更详细的纵向免疫分析，以回答几个问题，旨在指导未来临床试验的疫苗接种的最佳时间表。我们报告了在12个人类白细胞抗原A2表达个体中的7个中，抗原特异性细胞溶解性T细胞应答在免疫后被扩增，并且多次免疫似乎是引发PAP特异性γ-干扰素分泌免疫应答所必需的，所述免疫应答可通过酶联免疫吸附斑点试验检测。此外，在前列腺特异性抗原倍增时间增加≥200%的个体中，8例中有6例可检测到长期PAP特异性γ-干扰素分泌T细胞应答，但14例中仅1例未观察到前列腺特异性抗原倍增时间变化（P=0.001）。最后，我们发现，免疫反应引发可以进一步放大随后的加强免疫。这些结果表明，未来的试验使用这种DNA疫苗，以及潜在的其他抗肿瘤DNA疫苗，可以研究定期加强免疫的持续给药时间表。此外，这些结果表明，靶向PAP的DNA疫苗可能与其他疫苗在异源免疫策略中组合，以进一步增强PAP特异性T细胞免疫。
Prostatic acid phosphatase (PAP) is a tumor antigen in prostate cancer and the target of several anti-tumor vaccines in earlier clinical trials. Ultimately, the goal of anti-tumor vaccines is to elicit a sustainable immune response, able to eradicate a tumor, or at least restrain its growth. We have investigated plasmid DNA vaccines and have previously conducted a phase 1 trial in which patients with recurrent prostate cancer were vaccinated with a DNA vaccine encoding PAP. In this study, we investigated the immunologic efficacy of subsequent booster immunizations, and conducted more detailed longitudinal immune analysis, to answer several questions aimed at guiding optimal schedules of vaccine administration for future clinical trials. We report that antigen-specific cytolytic T-cell responses were amplified after immunization in 7 of 12 human leukocyte antigen-A2-expressing individuals, and that multiple immunizations seemed necessary to elicit PAP-specific interferon-γ-secreting immune responses detectable by enzyme-linked immunosorbent spot assay. Moreover, among individuals who experienced a ≥200% increase in prostate-specific antigen doubling time, long-term PAP-specific interferon-γ-secreting T-cell responses were detectable in 6 of 8, but in only 1 of 14 individuals without an observed change in prostate-specific antigen doubling time (P=0.001). Finally, we identified that immune responses elicited could be further amplified by subsequent booster immunizations. These results suggest that future trials using this DNA vaccine, and potentially other anti-tumor DNA vaccines, could investigate ongoing schedules of administration with periodic booster immunizations. Moreover, these results suggest that DNA vaccines targeting PAP could potentially be combined in heterologous immunization strategies with other vaccines to further augment PAP-specific T-cell immunity.