The University of Texas MD Anderson Cancer Center Department of Thoracic Head and Neck Medical Oncology, Houston, Texas, USA.
Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Immunother Cancer. 2022 Feb;10(2). doi: 10.1136/jitc-2021-004232.
The combination of ISA101, a human papilloma virus (HPV) 16 peptide vaccine, and nivolumab showed a promising response rate of 33% in patients with incurable HPV-16 cancer. Here we report long-term clinical outcomes and immune correlates of response.
Patients with advanced HPV-16 cancer and less than two prior regimens for recurrence were enrolled to receive ISA101 (100 µg/peptide) on days 1, 22, and 50 and nivolumab 3 mg/kg every 2 weeks beginning day 8 for up to 1 year. Baseline tumor samples were stained with multiplex immunofluorescence for programmed death-ligand 1 (PD-L1), programmed cell death protein-1 (PD-1), CD3, CD8, CD68, and pan-cytokeratin in a single panel and scanned with the Vectra 3.0 multispectral microscope. Whole transcriptome analysis of baseline tumors was performed with Affymetrix Clariom D arrays. Differential gene expression analysis was performed on responders versus non-responders.
Twenty-four patients were followed for a median of 46.5 months (95% CI, 46.0 months to not reached (NR)). The median duration of response was 11.2 months (95% CI, 8.51 months to NR); three out of eight (38%) patients with objective response were without progression at 3 years. The median and 3-year overall survival were 15.3 months (95% CI, 10.6 months to 27.2 months) and 12.5% (95% CI, 4.3% to 36%), respectively. The scores for activated T cells ((CD3PD-1)+(CD3CD8PD-1)), activated cytotoxic T cells (CD3CD8PD-1), and total macrophage ((CD68PD-L1)+(CD68PD-L1)) in tumor were directly correlated with clinical response (p<0.05) and depth of response with the two complete response patients having the highest degree of CD8 T cells. Gene expression analysis revealed differential regulation of 357 genes (≥1.25 fold) in non-responders versus responders (p<0.05). Higher expression of immune response, inflammatory response and interferon-signaling pathway genes were correlated with clinical response (p<0.05).
Efficacy of ISA101 and nivolumab remains promising in long-term follow-up. Increased infiltration by PD-1 T cells and macrophages was predictive of response. Enrichment in gene sets associated with interferon-γ response and immune infiltration strongly predicted response to therapy. A randomized trial is ongoing to test this strategy and to further explore correlates of immune response with combined nivolumab and ISA101, versus nivolumab alone.
NCT02426892.
ISA101（一种人乳头瘤病毒（HPV）16 肽疫苗）与纳武利尤单抗联合使用，在无法治愈的 HPV-16 癌症患者中显示出 33%的有希望的反应率。在此，我们报告长期临床结果和免疫反应相关因素。
招募患有晚期 HPV-16 癌症且复发前不到两种治疗方案的患者，接受 ISA101（100μg/肽），在第 1、22 和 50 天，nivolumab 3mg/kg 每 2 周一次，从第 8 天开始，最长可达 1 年。在单个面板中使用多重免疫荧光法对基线肿瘤样本进行程序性死亡配体 1（PD-L1）、程序性细胞死亡蛋白-1（PD-1）、CD3、CD8、CD68 和泛细胞角蛋白染色，并使用 Vectra 3.0 多光谱显微镜进行扫描。使用 Affymetrix Clariom D 阵列对基线肿瘤进行全转录组分析。对反应者与非反应者进行差异基因表达分析。
24 例患者中位随访 46.5 个月（95%CI，46.0 个月至未达到（NR））。中位缓解持续时间为 11.2 个月（95%CI，8.51 个月至 NR）；8 例客观反应患者中有 3 例在 3 年内无进展。中位总生存期和 3 年总生存期分别为 15.3 个月（95%CI，10.6 个月至 27.2 个月）和 12.5%（95%CI，4.3%至 36%）。肿瘤中活化 T 细胞（（CD3PD-1）+（CD3CD8PD-1））、活化细胞毒性 T 细胞（CD3CD8PD-1）和总巨噬细胞（（CD68PD-L1）+（CD68PD-L1））评分与临床反应直接相关（p<0.05），与两名完全缓解患者的反应深度与 CD8 T 细胞的程度最高相关。基因表达分析显示，非反应者与反应者之间有 357 个基因（≥1.25 倍）差异调节（p<0.05）。免疫反应、炎症反应和干扰素信号通路基因的高表达与临床反应相关（p<0.05）。
ISA101 和纳武利尤单抗的疗效在长期随访中仍然很有希望。PD-1 T 细胞和巨噬细胞浸润增加是反应的预测因素。与干扰素-γ反应和免疫浸润相关的基因集的富集强烈预测了对治疗的反应。一项正在进行的随机试验旨在测试这种策略，并进一步探索联合使用纳武利尤单抗和 ISA101 与单独使用纳武利尤单抗的免疫反应相关因素。
NCT02426892。
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