Hydrodynamic limb vein delivery of a xenogeneic DNA cancer vaccine effectively induces antitumor immunity.
Hydrodynamic limb vein delivery of a xenogeneic DNA cancer vaccine effectively induces antitumor immunity.
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DOI：
10.1038/sj.mt.6300046
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发表时间：
2007-02
期刊：
影响因子：
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通讯作者：
Z. Neal;M. Bates;M. Albertini;H. Herweijer
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文献类型：
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作者：
Z. Neal;M. Bates;M. Albertini;H. Herweijer
肿瘤相关抗原（TAA）通常是免疫原性较差的“自身”抗原。打破耐受性并诱导抗肿瘤免疫的有效策略是通过基因疫苗接种，使用来自不同物种的直系同源 TAA 序列。我们最近开发了一种临床相关的方法，用于通过血管内流体动力学肢体静脉 (HLV) 将核酸递送至骨骼肌。在鼠 B16 黑色素瘤模型中使用人 gp100 异种 TAA，我们发现通过 HLV 质粒 DNA 递送对小鼠进行基因疫苗接种可以非常有效地打破对同源鼠 gp100 (mgp100) TAA 的耐受性并诱导预防性抗肿瘤保护。 HLV 疫苗接种导致抗 hgp100 体液和细胞反应，其中 4-5% 的 CD8+T 细胞具有 gp10025-33 表位特异性。接种疫苗的动物表现出针对人类和 mgp10025-33 肽脉冲靶标的体内细胞溶解活性。抗肿瘤免疫力可以通过接种人类 gp100 的动物的脾细胞过继转移。此外，在接种疫苗 6 个月后，小鼠体内约 3% 的 CD8+T 细胞具有 gp10025-33 抗原特异性，从而建立了持久的抗肿瘤记忆反应。在单次 HLV 人类 gp100 DNA 增强后，该水平增加至约 17%，并保护动物免受随后的 B16 肿瘤再次攻击。我们的结果值得进一步考虑 HLV 作为癌症基因治疗的临床相关方法。
Tumor-associated antigens (TAA) are typically poorly immunogenic "self" antigens. An effective strategy to break tolerance and induce antitumor immunity is by genetic vaccination, employing the orthologous TAA-sequence from a different species. We recently developed a clinically relevant approach for intravascular hydrodynamic limb vein (HLV) delivery of nucleic acids to skeletal muscle. Using the human gp100 xenogeneic TAA in the murine B16 melanoma model, we show that genetic vaccination of mice by HLV plasmid DNA delivery was highly effective at breaking tolerance against the homologous murine gp100 (mgp100) TAA and induced prophylactic antitumor protection. HLV vaccination resulted in an anti-hgp100 humoral and cellular response, with 4–5% of CD8+T cells being gp10025–33-epitope-specific. Vaccinated animals demonstratedin vivocytolytic activity against human and mgp10025–33peptide-pulsed targets. Antitumor immunity could be adoptively transferred by splenocytes from human gp100-vaccinated animals. Furthermore, a durable antitumor memory response was established as ∼3% of CD8+T cells were gp10025–33antigen-specific in mice 6 months after vaccination. Following a single HLV human gp100 DNA boost, this level increased to ∼17% and protected animals from subsequent B16 tumor rechallenge. Our results warrant further consideration of HLV as a clinically relevant method for cancer gene therapy.