Abstract

Background

Anal high-grade intraepithelial lesions (HSIL) precede the development of HPV-associated anal cancer and so present a target for early intervention and cancer prevention. Spontaneous HSIL clearance is associated with systemic CD4 T-cell response to the HPV oncogene E6. Pomalidomide may enhance immune responses to HPV and be therapeutic in HSIL.

Methods

This phase II single centre study (NCT3113942) recruited participants with persistent (>12 months) biopsy-proven anal HSIL. Therapy was oral pomalidomide, 2mg for 21 of 28 days for up to 6 months. Primary outcome was response at end therapy (CR defined as histological clearance; PR as ≥ 50% reduction in area); secondary included response after 6 further months observation. Immune activation markers (CD38, HLA DR) were assessed with flow cytometry and antigen-specific CD4+ T-cell responses to HPV E6 and E7 with OX40 immunoassay.

Results

26 participants were enrolled, 24 were evaluable for response. All male; median age 54 (range 41-74). All AIN3 HSIL, median duration HSIL 37 months (15-86), median octants 2 (0.5-5); HPV16 in 55%; multiple high risk HPV types in 50%. Overall response (CR+PR) was 52% (CI: 31-73) at end therapy, increasing to 63% (95% CI 40-81) after 6 further months observation. Adverse events (AEs) were mild and self-limited, including cytopenias, constipation, and rash. Over 137 cycles (c), attributable grade 3/4 events were grade 3 neutropenia (4 c) and grade 3 angina (1 c). Systemic CD4 T-cell responses to HPV E6 but not E7 increased significantly during therapy, peaking day 14 of therapy: baseline 0.06%, (IQR 0.01 – 0.12%), median increase day 14 0.13% (IQR: 0.02 – 0.26%), p = 0.001. Activation of CD4 and CD8 cells increased significantly during therapy. Parameters returned to baseline after therapy.

Conclusion

Low dose oral pomalidomide was well tolerated and induced durable continuing clearance of anal HSIL of multiple genotypes in even in chronic extensive disease. Induction of HPV-specific CD4+ responses and immune activation support an immunological mechanism of action. Immunotherapy with pomalidomide is a promising approach to prevention of anal cancer and potentially other HPV cancers.

Clinical trial identification

NCT3113942.

Legal entity responsible for the study

Kirby Institute, University of New South Wales, Sydney, Australia.

Funding

Cancer Institute of New South Wales.

Disclosure

All authors have declared no conflicts of interest.

中文翻译：

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低剂量pomalidomide对HPV肛门癌前病变的清除96P和对HPV癌基因的全身免疫应答的调节

抽象的

背景

肛门上皮内高度病变（HSIL）早于HPV相关的肛门癌的发展，因此是早期干预和预防癌症的目标。自发性HSIL清除与系统CD4 T细胞对HPV癌基因E6的反应有关。泊马度胺可能增强对HPV的免疫反应，并在HSIL中具有治疗作用。

方法

这项II期单中心研究（NCT3113942）招募了经活检证实为持续性（> 12个月）的肛门HSIL的参与者。治疗方法是口服泊马利度胺，口服28天中的21mg，持续6个月。主要结局是结束治疗时的反应（CR定义为组织学清除率； PR定义为面积减少≥50％）；在进一步观察6个月后，继发性包括反应。通过流式细胞术评估免疫激活标记（CD38，HLA DR），并通过OX40免疫分析评估抗原特异性CD4 + T细胞对HPV E6和E7的反应。

结果

招募了26位参与者，其中24位是可评估的。全是男性；中位年龄54岁（范围41-74）。所有AIN3 HSIL，HSIL中位数持续时间37个月（15-86），八分位数中位数2（0.5-5）; HPV16占55％；50％的多种高危HPV类型。结束治疗后的总缓解率（CR + PR）为52％（CI：31-73），再观察6个月后增加至63％（95％CI 40-81）。不良事件（AE）轻微且自限，包括血细胞减少，便秘和皮疹。在137个周期（c）中，归因于3/4级事件是3级中性粒细胞减少（4 c）和3级心绞痛（1 c）。在治疗的第14天达到峰值时，对HPV E6的系统性CD4 T细胞反应显着增加，但对E7却没有明显增加：基线为0.06％，（IQR 0.01 – 0.12％），第14天的中位数增加为0.13％（IQR：0.02 – 0.26％）， p ＝ 0.001。在治疗过程中，CD4和CD8细胞的激活显着增加。

结论

即使在慢性广泛性疾病中，小剂量口服波马洛度也具有良好的耐受性，并能持续持久清除多种基因型的肛门HSIL。HPV特异性CD4 +应答的诱导和免疫激活支持免疫作用机制。泊马度胺的免疫疗法是预防肛门癌和其他潜在HPV癌症的有前途的方法。

临床试验鉴定

NCT3113942。

负责研究的法人实体

澳大利亚新南威尔士大学柯比研究所。

资金

新南威尔士州癌症研究所。

揭露

所有作者均声明没有利益冲突。