Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16-Related Cancer A Phase 2 Clinical Trial
Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16-Related Cancer A Phase 2 Clinical Trial
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DOI：
10.1001/jamaoncol.2018.4051
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发表时间：
2019-01-01
期刊：
影响因子：
28.4
通讯作者：
Glisson, Bonnie
中科院分区：
文献类型：
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作者：
Massarelli, Erminia;William, William;Glisson, Bonnie
在复发性人乳头瘤病毒（HPV）驱动的癌症中，使用抗程序性细胞死亡1（PD-1）抗体的免疫检查点阻断仅在少数患者中产生肿瘤消退。治疗性HPV疫苗对HPV-16产生了强烈的免疫应答，但单独接种疫苗对浸润性癌症无效。目的确定抗PD-1免疫检查点抗体nivolumab的疗效是否通过伊萨101（一种诱导HPV-16特异性T细胞的合成长肽HPV-16疫苗）治疗不可治愈的HPV-16阳性癌症患者而增强。在这项单组、单中心的2期临床试验中，2015年12月23日至2016年12月12日，24例HPV-16阳性癌症患者入组。对删失患者的随访持续时间为12.2个月，至2017年8月31日。干预在第1、22和50天皮下注射疫苗ISA 101，100 μ g/肽。从第8天开始每2周一次静脉内给予Nivolumab，3 mg/kg，长达1年。（根据实体瘤疗效评价标准，版本1.1）。（4名女性和20名男性; 22名口咽癌患者;中位年龄60岁[范围，36-73岁]），总体缓解率为33%（8名患者; 90%CI，19%-50%）。中位缓解持续时间为10.3个月（95% CI，10.3个月至无法估计）。8名患者中有5名仍有反应。中位无进展生存期为2.7个月（95% CI，2.5-9.4个月）。中位总生存期为17.5个月（95% CI，17.5个月至无法估计）。2例患者发生3 - 4级毒性反应（1例患者无症状3级转氨酶水平升高，1例患者4级脂肪酶升高），需要停止nivolumab therapeutic.CONCLUSIONS AND RELEVANCE与PD-1单独抑制相比，33%的总体缓解率和17.5个月的中位总生存期是有希望的。一项随机临床试验证实了HPV-16疫苗接种对PD-1抑制的杀肿瘤作用的贡献，需要进一步研究。
IMPORTANCE In recurrent human papilloma virus (HPV)-driven cancer, immune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies produces tumor regression in only a minority of patients. Therapeutic HPV vaccines have produced strong immune responses to HPV-16, but vaccination alone has been ineffective for invasive cancer.OBJECTIVE To determine whether the efficacy of nivolumab, an anti-PD-1 immune checkpoint antibody, is amplified through treatment with ISA 101, a synthetic long-peptide HPV-16 vaccine inducing HPV-specific T cells, in patients with incurable HPV-16-positive cancer.DESIGN, SETTING, AND PARTICIPANTS In this single-arm, single-center phase 2 clinical trial, 24 patients with incurable HPV-16-positive cancer were enrolled from December 23, 2015, to December 12, 2016. Duration of follow-up for censored patients was 12.2 months through August 31, 2017.INTERVENTIONS The vaccine ISA101, 100 mu g/peptide, was given subcutaneously on days 1, 22, and 50. Nivolumab, 3 mg/kg, was given intravenously every 2 weeks beginning day 8 for up to 1 year.MAIN OUTCOMES AND MEASURES Assessment of efficacy reflected in the overall response rate (per Response Evaluation Criteria in Solid Tumors, version 1.1).RESULTS Of the 24 patients (4 women and 20 men; 22 with oropharyngeal cancer; median age, 60 years [range, 36-73 years]), the overall response rate was 33%(8 patients; 90% CI, 19%-50%). Median duration of response was 10.3 months (95% CI, 10.3 months to inestimable). Five of 8 patients remain in response. Median progression-free survival was 2.7 months (95% CI, 2.5-9.4 months). Median overall survival was 17.5 months (95% CI, 17.5 months to inestimable). Grades 3 to 4 toxicity occurred in 2 patients (asymptomatic grade 3 transaminase level elevation in 1 patient and grade 4 lipase elevation in 1 patient), requiring discontinuation of nivolumab therapy.CONCLUSIONS AND RELEVANCE The overall response rate of 33% and median overall survival of 17.5 months is promising compared with PD-1 inhibition alone in similar patients. A randomized clinical trial to confirm the contribution of HPV-16 vaccination to tumoricidal effects of PD-1 inhibition is warranted for further study.