Abstract：
Human papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventive vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8+ T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections.
摘要：
人乳头瘤病毒(HPV)16和18感染与许多人类癌症有关。尽管有几种针对高风险（hr）HPV的预防性疫苗，仍然迫切需要开发用于靶向预先存在的hrHPV感染和病变的治疗性HPV疫苗.在这项研究中,我们开发了一种脂质纳米颗粒(LNP)配制的基于mRNA的HPV治疗性疫苗(mHTV)-03E2,同时靶向HPV16和HPV18的E2/E6/E7.mHTV-03E2显著诱导抗原特异性细胞免疫反应，在来自表达HPVE6/E7抗原的C57BL/6小鼠的原代肺上皮细胞的TC-1肿瘤中导致显著的CD8+T细胞浸润和细胞毒性，介导的显著肿瘤消退，延长动物的存活时间,以剂量依赖的方式。在免疫和远处肿瘤挑战实验中，我们进一步证明了针对HPV16/18E6/E7抗原的显著T细胞免疫接种后长达4个月，提示针对复发的健壮记忆T细胞免疫。最后,mHTV-03E2与免疫检查点阻断协同抑制肿瘤生长并延长动物存活，表明联合治疗的潜力。我们得出的结论是，mHTV-03E2是治疗由HPV16或HPV18感染引起的恶性肿瘤的出色候选治疗性mRNA疫苗。
