Elzey B D, Siemens D R, Ratliff T L, Lubaroff D M
Department of Microbiology, University of Iowa, Iowa City, IA 55242, USA.
Int J Cancer. 2001 Dec 15;94(6):842-9. doi: 10.1002/ijc.1556.
Prostate-specific antigen (PSA) is expressed by prostate epithelial cells and has a highly restricted tissue distribution. Prostatic malignancies in 95% of patients continue to express PSA, making this antigen a good candidate for targeted immunotherapy. The goals of our studies are to generate a recombinant PSA adenovirus type 5 (Ad5-PSA) that is safe and effectively activates a PSA-specific T-cell response capable of eliminating prostate cancer cells, and to characterize the immunologic basis for this rejection. Here we show that immunization of mice with Ad5-PSA induced PSA-specific cellular and humoral immunity that was protective against a subcutaneous challenge with RM11 prostate cancer cells expressing PSA (RM11psa), but not mock-transfected RM11 tumor cells (RM11neo). Mice immunized with recombinant adenovirus type 5 encoding beta-galactosidase (Ad5-lacZ) did not generate protective immunity. Antitumor activity was predominantly mediated by CD8(+) T lymphocytes. Although Ad5-PSA immunization prior to RM11psa challenge was protective, Ad5-PSA immunization alone was not able to control the growth of existing RM11psa tumors. In contrast, established RM11psa tumors ranging in size from 500 to 1,000 mm(3) were efficiently eliminated if Ad5-PSA priming was followed 7 days later by intratumoral injection of recombinant canarypox viruses (ALVAC) encoding interleukin-12 (IL-12), IL-2, and tumor necrosis factor-alpha. In this case, antitumor immunity was still dominated by CD8(+) T lymphocytes, but natural killer cells became necessary for a maximal response. These data provide information on the effector cell populations in a protective immune response to prostate cancer and demonstrate the utility of an Ad5-PSA vaccine combined with cytokine gene delivery to eliminate large established tumors that are refractory to other interventional methods.
前列腺特异性抗原（PSA）由前列腺上皮细胞表达，且组织分布高度受限。95%的前列腺癌患者体内的前列腺恶性肿瘤会持续表达PSA，这使得该抗原成为靶向免疫治疗的理想候选对象。我们研究的目标是构建一种安全且能有效激活PSA特异性T细胞反应以消除前列腺癌细胞的重组5型PSA腺病毒（Ad5-PSA），并阐明这种排斥反应的免疫学基础。在此我们表明，用Ad5-PSA免疫小鼠可诱导PSA特异性细胞免疫和体液免疫，这种免疫对皮下接种表达PSA的RM11前列腺癌细胞（RM11psa）具有保护作用，但对 mock 转染的RM11肿瘤细胞（RM11neo）则无保护作用。用编码β-半乳糖苷酶的重组5型腺病毒（Ad5-lacZ）免疫的小鼠未产生保护性免疫。抗肿瘤活性主要由CD8(+) T淋巴细胞介导。虽然在接种RM11psa之前用Ad5-PSA免疫具有保护作用，但单独使用Ad5-PSA免疫无法控制已存在的RM11psa肿瘤的生长。相比之下，如果在Ad5-PSA启动免疫7天后瘤内注射编码白细胞介素-12（IL-12）、IL-2和肿瘤坏死因子-α的重组金丝雀痘病毒（ALVAC），则大小在500至1000立方毫米之间的已建立的RM11psa肿瘤可被有效消除。在这种情况下，抗肿瘤免疫仍以CD8(+) T淋巴细胞为主，但自然杀伤细胞对于最大反应变得必不可少。这些数据提供了关于前列腺癌保护性免疫反应中效应细胞群体的信息，并证明了Ad5-PSA疫苗与细胞因子基因递送相结合以消除对其他干预方法难治的大型已建立肿瘤的效用。
