Braun Molly R, Moore Anne C, Lindbloom Jonathan D, Hodgson Katherine A, Dora Emery G, Tucker Sean N
Vaxart Inc., 170 Harbor Way Suite 300, South San Francisco, CA 94080, USA.
School of Biochemistry and Cell Biology, University College Cork, T12 XF62 Cork, Ireland.
Vaccines (Basel). 2024 Aug 23;12(9):955. doi: 10.3390/vaccines12090955.
Therapeutic vaccination can harness the body's cellular immune system to target and destroy cancerous cells. Several treatment options are available to eliminate pre-cancerous and cancerous lesions caused by human papillomaviruses (HPV), but may not result in a long-term cure. Therapeutic vaccination may offer an effective, durable, and minimally intrusive alternative. We developed mucosally delivered, recombinant, non-replicating human adenovirus type 5 (rAd5)-vectored vaccines that encode HPV16's oncogenic proteins E6 and E7 alongside a molecular dsRNA adjuvant. The induction of antigen-specific T cells and the therapeutic efficacy of rAd5 were evaluated in a mouse model of HPV tumorigenesis where E6E7-transformed cells, TC-1, were implanted subcutaneously in C57BL/6 mice. After tumor growth, mice were treated intranasally with rAd5 vaccines expressing the wildtype form of E6E7 (rAd5-16/E6E7) in combination with an anti-PD-1 antibody or isotype control. Animals treated with rAd5-16/E6E7 with and without anti-PD-1 had significant reductions in tumor volume and increased survival compared to controls. Further, animals treated with rAd5-16/E6E7 had increased CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) and produced a cytotoxic tumor microenvironment. In a second study, the immunogenicity of a non-transformative form of E6E7 (rAd5-16/E6E7) and a vaccine encoding predicted T cell epitopes of E6E7 (rAd5-16/E6E7) were evaluated. These vaccines elicited significant reductions in TC-1 tumor volume and increased survival of animals. Antigen-specific CD8+ T effector memory cells were observed in the animals treated with E6E7-encoding rAd5, but not in the rAd5-empty group. The work described here demonstrates that this mucosal vaccination can be used therapeutically to elicit specific cellular immunity and further identifies a clinical candidate with great potential for the treatment and prevention of human cervical cancer.
治疗性疫苗接种可以利用人体的细胞免疫系统来靶向并摧毁癌细胞。有几种治疗方案可用于消除由人乳头瘤病毒（HPV）引起的癌前病变和癌变，但可能无法实现长期治愈。治疗性疫苗接种可能提供一种有效、持久且侵入性最小的替代方案。我们开发了通过黏膜递送的、重组的、非复制型人5型腺病毒（rAd5）载体疫苗，其编码HPV16的致癌蛋白E6和E7以及一种分子双链RNA佐剂。在HPV肿瘤发生的小鼠模型中评估了抗原特异性T细胞的诱导以及rAd5的治疗效果，在该模型中，将E6E7转化的细胞TC-1皮下植入C57BL/6小鼠体内。肿瘤生长后，用表达野生型E6E7形式的rAd5疫苗（rAd5-16/E6E7）联合抗PD-1抗体或同型对照对小鼠进行鼻内治疗。与对照组相比，接受rAd5-16/E6E7联合或不联合抗PD-1治疗的动物肿瘤体积显著减小，生存期延长。此外，接受rAd5-16/E6E7治疗的动物肿瘤浸润淋巴细胞（TILs）中的CD4+和CD8+增加，并产生了细胞毒性肿瘤微环境。在第二项研究中，评估了非转化形式的E6E7（rAd5-16/E6E7）和编码E6E7预测T细胞表位的疫苗（rAd5-16/E6E7）的免疫原性。这些疫苗使TC-1肿瘤体积显著减小，动物生存期延长。在用编码E6E7的rAd5治疗的动物中观察到了抗原特异性CD8+T效应记忆细胞，而在rAd5空载体组中未观察到。此处描述的工作表明，这种黏膜疫苗接种可用于治疗性诱导特异性细胞免疫，并进一步确定了一种在治疗和预防人类宫颈癌方面具有巨大潜力的临床候选疫苗。
