Safety and immunologic response of a viral vaccine to prostate-specific antigen in combination with radiation therapy when metronomic-dose interleukin 2 is used as an adjuvant.
Safety and immunologic response of a viral vaccine to prostate-specific antigen in combination with radiation therapy when metronomic-dose interleukin 2 is used as an adjuvant.
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DOI：
10.1158/1078-0432.ccr-07-5162
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发表时间：
2008-08-15
影响因子：
11.5
通讯作者：
Gulley, James L.
中科院分区：
文献类型：
--
作者：
Lechleider, Robert J.;Arlen, Philip M.;Tsang, Kwong-Yok;Steinberg, Seth M.;Yokokawa, Junko;Cereda, Vittore;Camphausen, Kevin;Schlom, Jeffrey;Dahut, William L.;Gulley, James L.
我们之前曾报道过一种基于痘病毒的编码PSA疫苗与放射治疗联合用于局限性前列腺癌患者的安全性和免疫反应。我们假设，“节拍”剂量的IL-2作为生物佐剂，在保持免疫反应的同时，会引起更小的毒性。在一项单臂试验中，18名局部前列腺癌患者使用先前确定的疫苗剂量和放射治疗进行治疗。使用的疫苗是编码PSA的重组痘苗病毒（rV）与编码共刺激分子B7.1的rV混合，然后用表达PSA的重组鸡痘载体加强接种。患者共接受了8个计划接种周期，每4周接种一次，GM-CSF在每次接种后的第1至4天接种，IL-2在每次接种后的第8至21天接种，剂量为0.6 MIU/M2。在第三个疫苗接种周期后开始进行最终的外束放射治疗。评估患者的安全性和免疫反应。毒性和免疫活性与先前报道的含有较高剂量IL-2的方案进行了比较。18例患者中有17例接受了所有8个周期的IL-2疫苗。8例HLA-A2+患者中有5例psa特异性T细胞增加≥3倍。毒性一般较轻，140次接种周期中仅有7次可能由IL-2引起3级毒性。节拍剂量IL-2与疫苗和放射治疗联合使用是安全的，可以诱导前列腺特异性免疫反应，并且具有与低剂量IL-2相似的免疫活性，毒性明显降低。
We have previously reported on the safety and immunological response of a poxvirus-based vaccine encoding PSA used in combination with radiation therapy in patients with localized prostate cancer. We hypothesized that a “metronomic” dose of IL-2 as a biologic adjuvant would cause less toxicity while maintaining immunological response. Eighteen patients with localized prostate cancer were treated in a single-arm trial using previously established doses of vaccine and radiation therapy. The vaccine used was a recombinant vaccinia (rV) virus engineered to encode PSA admixed with an rV encoding the costimulatory molecule B7.1, followed by booster vaccinations with a recombinant fowlpox vector expressing PSA. Patients received a total of 8 planned vaccination cycles, once every 4 weeks, with GM-CSF administered on days 1 to 4 and IL-2 at a dose of 0.6 MIU/M2 administered from days 8 to 21 following each vaccination. Definitive external beam radiation therapy was initiated following the third vaccination cycle. Patients were evaluated for safety and immunological response. Toxicity and immunological activity were compared to the previously reported regimen containing a higher dose of IL-2. Seventeen of 18 patients received all 8 cycles of vaccine with IL-2. Five of 8 HLA-A2+ patients evaluated had an increase in PSA-specific T cells of ≥ 3-fold. Toxicities were generally mild, with only 7 vaccination cycles out of 140 administered resulting in grade 3 toxicities possibly attributable to IL-2. Metronomic-dose IL-2 in combination with vaccine and radiation therapy is safe, can induce prostate-specific immune responses, and has immunologic activity similar to low-dose IL-2, with markedly reduced toxicities.