Characterization of recombinant gorilla adenovirus HPV therapeutic vaccine PRGN-2009
Characterization of recombinant gorilla adenovirus HPV therapeutic vaccine PRGN-2009
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DOI：
10.1172/jci.insight.141912
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发表时间：
2021-04-08
期刊：
影响因子：
8
通讯作者：
Jochems, Caroline
中科院分区：
文献类型：
--
作者：
Pellom, Samuel T.;Rumfield, Claire Smalley;Jochems, Caroline
在美国，每年约有44，000例人乳头瘤病毒相关（HPV相关）癌症，最常见的是由HPV 16和18型引起。预防性疫苗通过HPV特异性抗体成功预防健康人感染HPV。然而，为了治疗已确定的HPV相关恶性肿瘤，需要新的治疗方法。在携带SiHa（一种人HPV 16（+）宫颈肿瘤）的NSG-β 2 m（-/-）外周血单核细胞人源化小鼠和/或在同基因HPV 16（+）TC-1模型中评估多种重组大猩猩腺病毒HPV疫苗构建体。PRGN-2009是一种治疗性大猩猩腺病毒HPV疫苗，含有病毒癌蛋白HPV 16/18 E6和E7的多个细胞毒性T细胞表位，包括T细胞增强子激动剂表位。PRGN-2009治疗减少了携带人宫颈肿瘤SiHa的人源化小鼠的肿瘤微环境中的肿瘤体积并增加了CD 8（+）和CD 4（+）T细胞。在同基因TC-1模型中，PRGN-2009单药治疗还减少了肿瘤体积和重量，产生了高水平的HPV 16 E6特异性T细胞，并增加了肿瘤微环境中的多功能CD 8（+）和CD 4（+）T细胞。这些研究为我们对治疗性大猩猩腺病毒HPV疫苗PRGN-2009的了解提供了第一次评价，显示出有希望的临床前抗肿瘤疗效和HPV特异性T细胞的诱导，沿着其在临床试验中评价的基本原理。
There are approximately 44,000 cases of human papillomavirus-associated (HPV-associated) cancer each year in the United States, most commonly caused by HPV types 16 and 18. Prophylactic vaccines successfully prevent healthy people from acquiring HPV infections via HPV-specific antibodies. In order to treat established HPV-associated malignancies, however, new therapies are necessary. Multiple recombinant gorilla adenovirus HPV vaccine constructs were evaluated in NSG-beta 2m(-/-) peripheral blood mononuclear cell-humanized mice bearing SiHa, a human HPV16(+) cervical tumor, and/or in the syngeneic HPV16(+) TC-1 model. PRGN-2009 is a therapeutic gorilla adenovirus HPV vaccine containing multiple cytotoxic T cell epitopes of the viral oncoproteins HPV 16/18 E6 and E7, including T cell enhancer agonist epitopes. PRGN-2009 treatment reduced tumor volume and increased CD8(+) and CD4(+) T cells in the tumor microenvironment of humanized mice bearing the human cervical tumor SiHa. PRGN-2009 monotherapy in the syngeneic TC-1 model also reduced tumor volumes and weights, generated high levels of HPV16 E6-specific T cells, and increased multifunctional CD8(+) and CD4(+) T cells in the tumor microenvironment. These studies provide the first evaluation to our knowledge of a therapeutic gorilla adenovirus HPV vaccine, PRGN-2009, showing promising preclinical antitumor efficacy and induction of HPV-specific T cells, along with the rationale for its evaluation in clinical trials.