Lubaroff David M, Karan Dev
Department of Urology, University of Iowa, Iowa City, 52242, United States.
Adv Drug Deliv Rev. 2009 Mar 28;61(3):268-74. doi: 10.1016/j.addr.2008.12.005. Epub 2009 Jan 7.
The use of an adenovirus transduced to express a prostate cancer antigen (PSA) as a vaccine for the treatment of prostate cancer has been shown to be active in the destruction of antigen-expressing prostate tumor cells in a pre-clinical model, using Balb/C or PSA transgenic mice. The destruction of PSA-secreting mouse prostate tumors was observed in Ad/PSA immunized mice in a prophylaxis study with 70% of the mice surviving long term tumor free. This successful immunotherapy was not observed in therapeutic studies in which tumors were established before vaccination and the development of anti-PSA immune response was not as easily generated in PSA transgenic mice. Immunization of conventional and transgenic animals was enhanced by incorporating a collagen matrix into the immunizing injection. Therefore the need to strengthen anti-PSA and anti-prostate cancer immunity was an obvious next step in developing a successful prostate cancer immunotherapy. Because the use of immunostimulatory CpG motifs was shown to enhance immune responses to a wide variety of antigens, our studies incorporated CpG into the Ad/PSA vaccine experimental plans. The results of the subsequent studies demonstrated a dichotomy where Ad/PSA plus CpG enhanced the in vivo destruction of PSA-secreting tumors and the survival of experimental animals, but revealed that the number and in vitro activities of antigen specific CD8+ T cells was decreased as compared to the values observed when the vaccine alone was used for immunization. The dichotomous observations were confirmed using another antigen system, OVA also incorporated into a replication defective adenovirus. Despite the reduction in antigen-specific CD8+ cells after vaccine plus CpG immunization the enhanced destruction of sc and systemic tumors was shown to be mediated entirely by CD8+ T cells. Finally, the reduction of the CD8+ T cells was the result of an observed decrease in the proliferation of the antigen specific cell population.
已证明，使用转导以表达前列腺癌抗原（PSA）的腺病毒作为治疗前列腺癌的疫苗，在临床前模型中，利用Balb/C或PSA转基因小鼠，可有效破坏表达抗原的前列腺肿瘤细胞。在一项预防研究中，观察到Ad/PSA免疫小鼠中分泌PSA的小鼠前列腺肿瘤被破坏，70%的小鼠长期无瘤存活。在治疗研究中未观察到这种成功的免疫疗法，在这些研究中，肿瘤在接种疫苗前已形成，且在PSA转基因小鼠中不易产生抗PSA免疫反应。通过在免疫注射中加入胶原蛋白基质，增强了对常规动物和转基因动物的免疫。因此，加强抗PSA和抗前列腺癌免疫是成功开发前列腺癌免疫疗法的下一步明显举措。由于已证明使用免疫刺激CpG基序可增强对多种抗原的免疫反应，我们的研究将CpG纳入Ad/PSA疫苗实验方案。后续研究结果显示出一种二分法，即Ad/PSA加CpG增强了分泌PSA肿瘤的体内破坏和实验动物的存活，但表明与单独使用疫苗进行免疫时观察到的值相比，抗原特异性CD8+T细胞的数量和体外活性有所下降。使用另一种也纳入复制缺陷腺病毒的抗原系统OVA证实了这些二分法观察结果。尽管疫苗加CpG免疫后抗原特异性CD8+细胞减少，但皮下和全身肿瘤的增强破坏显示完全由CD8+T细胞介导。最后，CD8+T细胞的减少是观察到的抗原特异性细胞群体增殖下降的结果。
