Suppr
超能文献

联合α肿瘤坏死因子基因治疗与工程化树突状细胞疫苗对抗已形成的肿瘤。

Combined alpha tumor necrosis factor gene therapy and engineered dendritic cell vaccine in combating well-established tumors.

作者信息

Liu Yongqing, Saxena Anurag, Zheng Changyu, Carlsen Svein, Xiang Jim

机构信息

Research Unit, Saskatchewan Cancer Agency, Departments of Microbiology, Immunology and Oncology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 4H4, Canada.

出版信息

J Gene Med. 2004 Aug;6(8):857-68. doi: 10.1002/jgm.576.

DOI:10.1002/jgm.576

PMID:15293344

Abstract

BACKGROUND

Although current immunotherapeutic strategies including adenovirus (AdV)-mediated gene therapy and dendritic cell (DC) vaccine can all stimulate antitumor cytotoxic T lymphocyte (CLT) responses, their therapeutic efficiency has still been limited to generation of prophylactic antitumor immunity against re-challenge with the parental tumor cells or growth inhibition of small tumors in vivo. However, it is the well-established tumors in animal models that mimic clinical patients with existing tumor burdens. Alpha tumor necrosis factor (TNF-alpha) is a multifunctional and immunoregulatory cytokine that induces antitumor activity and activates immune cells such as DCs and T cells. We hypothesized that a combined immunotherapy including gene therapy and DC vaccine would have some advantages over each modality administered as a monotherapy.

METHODS

We investigated the antitumor immunotherapeutic efficiency of gene therapy by intratumoral injection of AdVTNF-alpha and DC vaccine using subcutaneous injection of TNF-alpha-gene-engineered DC(TNF-alpha) cells, and further developed a combined AdV-mediated TNF-alpha-gene therapy and TNF-alpha-gene-engineered DC(TNF-alpha) vaccine in combating well-established MO4 tumors expressing the ovalbumin (OVA) gene in an animal model.

RESULTS

Our data show that vaccination of DC(TNF-alpha) cells pulsed with the OVA I peptide can (i) stimulate type 1 immune response with enhanced antitumor CTL activities, (ii) induce protective immunity against challenge of 5 x 10(5) MO4 tumor cells, and (iii) reduce growth of the small (3-4 mm in diameter), but not large, established MO4 tumors (6-8 mm in diameter). Our data also show that AdVTNF-alpha-mediated gene therapy can completely eradicate small tumors in 6 out of 8 (75%) mice due to the extensive tumor necrosis formation, but not the large tumors (0%). Interestingly, a combined AdVTNF-alpha-mediated gene therapy and TNF-alpha-gene-engineered DC(TNF-alpha) vaccine is able to cure 3 out of 8 (38%) mice bearing large MO4 tumors, indicating that the combined immunotherapy strategy is much more efficient in combating well-established tumors than monotherapy of either gene therapy or DC vaccine alone.

CONCLUSIONS

This novel combined immunotherapy may become a tool of considerable conceptual interest in the implementation of future clinical objectives.

摘要

背景

尽管当前的免疫治疗策略，包括腺病毒（AdV）介导的基因治疗和树突状细胞（DC）疫苗，都能刺激抗肿瘤细胞毒性T淋巴细胞（CLT）反应，但其治疗效果仍局限于产生针对亲本肿瘤细胞再次攻击的预防性抗肿瘤免疫，或在体内抑制小肿瘤的生长。然而，正是动物模型中已形成的肿瘤模拟了有现有肿瘤负荷的临床患者。α肿瘤坏死因子（TNF-α）是一种多功能免疫调节细胞因子，可诱导抗肿瘤活性并激活免疫细胞，如DC和T细胞。我们推测，包括基因治疗和DC疫苗的联合免疫疗法比单一疗法具有一些优势。

方法

我们通过瘤内注射AdVTNF-α研究基因治疗的抗肿瘤免疫治疗效果，并通过皮下注射TNF-α基因工程DC（TNF-α）细胞研究DC疫苗的效果，进而开发了一种联合AdV介导的TNF-α基因治疗和TNF-α基因工程DC（TNF-α）疫苗，用于对抗动物模型中表达卵清蛋白（OVA）基因的已形成的MO4肿瘤。

结果

我们的数据表明，用OVA I肽脉冲处理的DC（TNF-α）细胞接种可（i）通过增强抗肿瘤CTL活性刺激1型免疫反应，（ii）诱导针对5×10⁵个MO4肿瘤细胞攻击的保护性免疫，以及（iii）减少小的（直径3 - 4毫米）但不是大的已形成的MO4肿瘤（直径6 - 8毫米）的生长。我们的数据还表明，AdVTNF-α介导的基因治疗由于广泛的肿瘤坏死形成，可使8只小鼠中的6只（75%）的小肿瘤完全根除，但对大肿瘤则无效（0%）。有趣的是，联合AdVTNF-α介导的基因治疗和TNF-α基因工程DC（TNF-α）疫苗能够治愈8只携带大MO4肿瘤小鼠中的3只（38%），这表明联合免疫治疗策略在对抗已形成的肿瘤方面比单独的基因治疗或DC疫苗单一疗法更有效。