Immune Therapy Targeting E6/E7 Oncogenes of Human Papillomavirus Type 6 (HPV-6) Reduces or Eliminates the Need for Surgical Intervention in the Treatment of HPV-6 Associated Recurrent Respiratory Papillomatosis
Immune Therapy Targeting E6/E7 Oncogenes of Human Papillomavirus Type 6 (HPV-6) Reduces or Eliminates the Need for Surgical Intervention in the Treatment of HPV-6 Associated Recurrent Respiratory Papillomatosis
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DOI：
10.3390/vaccines8010056
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发表时间：
2020-03-01
期刊：
影响因子：
7.8
通讯作者：
Skolnik, Jeffrey M.
中科院分区：
文献类型：
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作者：
Aggarwal, Charu;Cohen, Roger B.;Skolnik, Jeffrey M.
背景：复发性呼吸道乳头状瘤病（RRP）是一种罕见的疾病，其特征是在空气消化道产生乳头状瘤，通常与人乳头状瘤病毒（HPV）亚型6,11有关。INO-3106是一种基于DNA质粒的免疫疗法，靶向HPV6的E6和E7蛋白，以产生强大的免疫T细胞应答。方法：动物模型检测INO-3016，证实其具有免疫原性。一项针对hpv6阳性RRP患者的单点开放标签i期研究启动。患者服用INO-3106或不服用INO-9012， INO-9012是一种编码IL-12的DNA质粒免疫疗法，结合电穿孔（EP）和CELLECTRA(R)装置肌肉注射（IM）。患者接受逐步递增剂量的INO-3106，一次3mg，然后再增加3次6mg，每次剂量间隔3周，第三次和第四次剂量与INO-9012共同给药。该研究的主要目的是评估INO-3106加和不加INO-9012的安全性和耐受性。次要目的是确定有或没有INO-9012时对INO-3106的细胞免疫反应。探索目标包括对治疗的初步临床疗效。结果：本研究纳入3例患者，其中2例有RRP。研究治疗耐受性良好，无相关严重不良事件，所有相关不良事件（ae）均为低级别。注射部位疼痛是最常见的AE相关报道。免疫原性通过多次免疫试验得到证实，显示参与和扩大了hpv6特异性细胞反应，包括细胞毒性T细胞。在RRP患者中证明了初步疗效，其形式是减少了对乳头状瘤生长的手术干预的需要。在干预之前，两名患者大约每180天需要一次手术干预。一名患者避免手术的时间增加了3倍以上（584天），另一名患者在最后一次接触时（915天）完全没有手术，手术间隔增加了5倍以上。结论：INO-3106合并或不合并INO-9012均具有良好的耐受性和免疫原性，对hpv6相关RRP气消化病变患者具有初步疗效。需要进一步的临床研究。
Background: Recurrent respiratory papillomatosis (RRP) is a rare disorder characterized by the generation of papillomas of the aerodigestive tract, usually associated with human papilloma virus (HPV) subtypes 6, 11. INO-3106 is a DNA plasmid-based immunotherapy targeting E6 and E7 proteins of HPV6, in order to create a robust immune T cell response. Methods: Testing of INO-3016 in animal models confirmed immunogenicity of the DNA-based therapy. A single-site open-label Phase 1 study was initiated for patients with HPV6-positive RRP. Patients were dosed with INO-3106 with or without INO-9012, a DNA plasmid immunotherapy that encodes IL-12, delivered intramuscularly (IM) in combination with electroporation (EP) with the CELLECTRA((R)) device. Patients received an escalating dose of INO-3106, 3 mg once and then 6 mg for three additional doses, each dose three weeks apart, with the third and fourth doses co-administered with INO-9012. The primary objective of the study was to evaluate the safety and tolerability of INO-3106 with and without INO-9012. The secondary objective was to determine cellular immune responses to INO-3106 with and without INO-9012. Exploratory objectives included preliminary clinical efficacy to the therapy. Results: Three patients were enrolled in this study, of which two had RRP. Study therapy was well-tolerated, with no related serious adverse events and all related adverse events (AEs) were low-grade. Injection site pain was the most common related AE reported. Immunogenicity was evidenced by multiple immune assays showing engagement and expansion of an HPV6-specific cellular response, including cytotoxic T cells. Preliminary efficacy was demonstrated in patients with RRP in the form of reduction in need for surgical intervention for papilloma growth. Prior to intervention, both patients required surgical intervention approximately every 180 days. One patient demonstrated a greater than three-fold increase in surgery avoidance (584 days) and the other patient remains completely surgery-free as of the last contact at 915 days, a greater than 5-fold increase in surgery interval. Conclusion: INO-3106 with and without INO-9012 was well tolerated, immunogenic and demonstrated preliminary efficacy in patients with HPV6-associated RRP aerodigestive lesions. Further clinical study is indicated.