Vaccine Development Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo , São Paulo, SP, 05508-900 Brazil .
Hum Gene Ther. 2013 Oct;24(10):861-70. doi: 10.1089/hum.2013.102.
Human papillomavirus (HPV) infection is responsible for all cervical cancer cases, other anogenital cancers, and head and neck tumors. The epidemiological relevance of HPV-induced tumors reinforces the need for the development of therapeutic antitumor vaccines. Clinical trials with different vaccine formulations, particularly DNA vaccines, have provided promising results but have still been unable to achieve the immunogenicity required for use in infected patients. In experimental conditions, anticancer HPV-specific vaccines induced E7-specific CD8(+) T-cell responses but did not confer full therapeutic antitumor protection in mice with transplanted HPV-expressing TC-1 cells, which are the most frequently used nonclinical protection correlate for antitumor effects. Our group has developed a DNA vaccine strategy based on the fusion of HPV oncoproteins to the herpes virus gD protein. This vaccine promoted the induction of antigen-specific cytotoxic CD8(+) T-cell responses and partial antitumor therapeutic effects based on the blockade of coinhibitory signals and the enhancement of coactivation mechanisms. In the present study, we report conditions leading to full therapeutic antitumor effects using the TC-1 cell murine model after a single vaccine dose. The combination of a coadministered plasmid encoding IL-2, optimization of the coding sequence for mammalian cells, and the use of different delivery routes resulted in enhancements of the E7-specific cytotoxic CD8(+) T-cell responses and full therapeutic protection under experimental conditions. The combination of these strategies augmented the potency of the DNA vaccine formulation to levels not previously achieved by other therapeutic antitumor vaccines under similar experimental conditions, including some that have been taken to clinical trials.
人乳头瘤病毒（HPV）感染是导致所有宫颈癌病例、其他肛门生殖器癌症以及头颈部肿瘤的原因。HPV 诱导肿瘤的流行病学相关性加强了开发治疗性抗肿瘤疫苗的必要性。不同疫苗制剂，特别是 DNA 疫苗的临床试验提供了有希望的结果，但仍未能达到用于感染患者的免疫原性要求。在实验条件下，抗癌 HPV 特异性疫苗诱导了 E7 特异性 CD8(+) T 细胞反应，但在移植了表达 HPV 的 TC-1 细胞的小鼠中并未提供完全的抗肿瘤保护作用，TC-1 细胞是最常用于抗肿瘤效果的非临床保护相关性的细胞。我们的小组开发了一种基于 HPV 致癌蛋白与疱疹病毒 gD 蛋白融合的 DNA 疫苗策略。该疫苗通过阻断共抑制信号和增强共激活机制，促进了抗原特异性细胞毒性 CD8(+) T 细胞反应的诱导和部分抗肿瘤治疗效果。在本研究中，我们报告了在单次疫苗剂量后，使用 TC-1 细胞小鼠模型实现完全抗肿瘤治疗效果的条件。共施用编码 IL-2 的质粒的组合、对哺乳动物细胞编码序列的优化以及不同传递途径的使用，导致了 E7 特异性细胞毒性 CD8(+) T 细胞反应的增强和在实验条件下的完全抗肿瘤保护。这些策略的结合增强了 DNA 疫苗制剂的效力，达到了在类似实验条件下以前其他治疗性抗肿瘤疫苗未达到的水平，包括一些已进入临床试验的疫苗。
