Immunization with type 5 adenovirus recombinant for a tumor antigen in combination with recombinant canarypox virus (ALVAC) cytokine gene delivery induces destruction of established prostate tumors
Immunization with type 5 adenovirus recombinant for a tumor antigen in combination with recombinant canarypox virus (ALVAC) cytokine gene delivery induces destruction of established prostate tumors
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DOI：
10.1002/ijc.1556
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发表时间：
2001-12-15
影响因子：
6.4
通讯作者：
Lubaroff, DM
中科院分区：
文献类型：
--
作者：
Elzey, BD;Siemens, DR;Lubaroff, DM
前列腺特异性抗原（PSA）由前列腺上皮细胞表达，并且具有高度受限的组织分布。 95% 的前列腺恶性肿瘤患者持续表达 PSA，使该抗原成为靶向免疫治疗的良好候选者。我们研究的目标是产生一种安全且有效地激活能够消除前列腺癌细胞的 PSA 特异性 T 细胞反应的重组 PSA 5 型腺病毒 (AdS-PSA)，并表征这种排斥的免疫学基础。在这里，我们表明，用 AdS-PSA 对小鼠进行免疫诱导了 PSA 特异性细胞和体液免疫，该免疫可以抵抗表达 PSA 的 RM11 前列腺癌细胞 (RM11psa) 的皮下攻击，但不能抵抗模拟转染的 RM11 肿瘤细胞 (RM11neo)。用编码β-半乳糖苷酶(Ad5-lacZ)的重组5型腺病毒免疫的小鼠没有产生保护性免疫力。抗肿瘤活性主要由CD8(+)T淋巴细胞介导。尽管在 RM11psa 攻击之前进行 Ad5-PSA 免疫具有保护性，但单独使用 Ad5-PSA 免疫无法控制现有 RM11psa 肿瘤的生长。相比之下，如果 Ad5-PSA 启动后 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)，则已建立的 RM11psa 肿瘤大小范围为 500 至 1,000 mm(3)，可被有效消除。在这种情况下，抗肿瘤免疫仍然以CD8+T淋巴细胞为主，但自然杀伤细胞成为最大反应所必需的。这些数据提供了有关前列腺癌保护性免疫反应中效应细胞群的信息，并证明了 Ad5-PSA 疫苗与细胞因子基因递送相结合的效用，可消除其他介入方法难以治疗的已形成的大型肿瘤。 (C) 2001 Wiley-Liss, Inc.
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 (AdS-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 AdS-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. (C) 2001 Wiley-Liss, Inc.