Therapeutic effects of adoptive splenocyte transfer following in situ AdIL-12 gene therapy in a mouse prostate cancer model
Therapeutic effects of adoptive splenocyte transfer following in situ AdIL-12 gene therapy in a mouse prostate cancer model
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DOI：
10.1038/sj.cgt.7700872
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发表时间：
2006-01-01
影响因子：
6.4
通讯作者：
Thompson, TC
中科院分区：
文献类型：
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作者：
Saika, T;Kusaka, N;Thompson, TC
我们建立了一个临床前前列腺癌模型，以研究新辅助原位腺病毒载体介导的白细胞介素12 （AdIL-12）基因治疗后残余肿瘤过继免疫治疗的可行性。脾细胞来自原位178-2 BMA转移性前列腺癌小鼠，先前用AdIL-12或IL-12基因加共刺激基因B7-1 （AdIL-12/B7）或对照基因（Ad β gal）治疗。随后将脾细胞静脉注射到携带3天前生成的原位178-2 BMA肿瘤的同基因小鼠中。与对照Ad β - gal小鼠的脾细胞相比，注射AdIL-12的小鼠的脾细胞显著抑制原位肿瘤的生长（P = 0.0005），而与对照小鼠的脾细胞相比，注射AdIL-12/ b7的小鼠的脾细胞显著抑制自发性肺转移（P = 0.0356）。与对照组相比，AdIL-12 （P = 0.004）或AdIL-12/B7 （P = 0.009）处理小鼠的脾细胞过继移植显著延长了生存期。检测NK和肿瘤特异性CTL活性的转移，并在注射前通过体外抗体介导的补体溶解脾细胞来消耗CD4+和CD8+ T细胞，消除了这种影响。肌内注射IL-12可增强过继性脾细胞移植的抗肿瘤作用，增强CTL反应。我们的数据提供了证据，证明这种形式的过继免疫治疗可以提高新辅助原位IL-12基因治疗在持续性恶性肿瘤中的有效性。
We developed a preclinical prostate cancer model to study the feasibility of adoptive immunotherapy for residual tumor following neo-adjuvant in situ adenoviral-vector-mediated interleukin 12 (AdIL-12) gene therapy. Splenocytes were obtained from mice with orthotopic 178-2 BMA metastatic mouse prostate cancers treated previously with AdIL-12, or a vector with the IL-12 genes plus the costimulatory gene B7-1 (AdIL-12/B7), or a control gene (Ad beta gal). The splenocytes were subsequently injected intravenously into syngeneic mice bearing orthotopic 178-2 BMA tumors generated 3 days previously. Significant orthotopic tumor growth suppression was achieved with splenocytes derived from mice whose tumors had been injected with AdIL-12 compared to splenocytes from control Ad beta gal mice ( P = 0.0005) and splenocytes from AdIL-12/B7-treated mice significantly suppressed spontaneous lung metastases compared to splenocytes from control mice ( P = 0.0356). Adoptive transfer of splenocytes from either AdIL-12 ( P = 0.004) or AdIL-12/B7 ( P = 0.009)-treated mice significantly prolonged survival relative to controls. Transfer of NK and tumor-specific CTL activities was detected and depletion of CD4+ and CD8+ T cells by in vitro antibody-mediated complement lysis of the splenocytes prior to injection abrogated the effects. Systemic IL-12 administration delivered by intramuscular AdIL-12 injection enhanced the antitumor effects of adoptive splenocyte transfer and boosted the CTL response. Our data provide evidence that this form of adoptive immunotherapy can enhance the effectiveness of neo-adjuvant in situ IL-12 gene therapy in cases of persistent malignancy.