McCann Katy J, Mander Ann, Cazaly Angelica, Chudley Lindsey, Stasakova Jana, Thirdborough Stephen, King Andrew, Lloyd-Evans Paul, Buxton Emily, Edwards Ceri, Halford Sarah, Bateman Andrew, O'Callaghan Ann, Clive Sally, Anthoney Alan, Jodrell Duncan I, Weinschenk Toni, Simon Petra, Sahin Ugur, Thomas Gareth J, Stevenson Freda K, Ottensmeier Christian H
Southampton Experimental Cancer Medicine Centre, Cancer Sciences Unit, University of Southampton, Southampton, UK.
University Hospital Southampton NHS Trust, Southampton, UK.
Clin Cancer Res. 2016 Oct 1;22(19):4827-4836. doi: 10.1158/1078-0432.CCR-15-2507. Epub 2016 Apr 18.
We have clinically evaluated a DNA fusion vaccine to target the HLA-A*0201-binding peptide CAP-1 from carcinoembryonic antigen (CEA) linked to an immunostimulatory domain (DOM) from fragment C of tetanus toxin.
Twenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (arm-I) and 12 patients without radiological evidence of disease (arm-II). Six intramuscular vaccinations of naked DNA (1 mg/dose) were administered up to week 12. Clinical and immunologic follow-up was up to week 64 or clinical/radiological disease.
DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared with 60% with advanced disease responded immunologically, while 58% and 20% expanded anti-CAP-1 CD8 T cells, respectively. CAP-1-specific T cells were only detectable in the blood postvaccination but could also be identified in previously resected cancer tissue. The gastrointestinal adverse event diarrhea was reported by 48% of patients and linked to more frequent decreases in CEA (P < 0.001) and improved global immunologic responses [anti-DOM responses of greater magnitude (P < 0.001), frequency (P = 0.004), and duration] compared with patients without diarrhea. In advanced disease patients, decreases in CEA were associated with better overall survival (HR = 0.14, P = 0.017). CAP-1 peptide was detectable on MHC class I of normal bowel mucosa and primary colorectal cancer tissue by mass spectrometry, offering a mechanistic explanation for diarrhea through CD8 T-cell attack.
Our data suggest that DNA vaccination is able to overcome peripheral tolerance in normal and tumor tissue and warrants testing in combination studies, for example, by vaccinating in parallel to treatment with an anti-PD1 antibody. Clin Cancer Res; 22(19); 4827-36. ©2016 AACR.
我们对一种DNA融合疫苗进行了临床评估，该疫苗靶向与破伤风毒素C片段的免疫刺激结构域（DOM）相连的癌胚抗原（CEA）的HLA - A*0201结合肽CAP - 1。
招募了27例表达CEA的癌症患者：15例有可测量疾病的患者（一组）和12例无疾病放射学证据的患者（二组）。在第12周前进行了6次裸DNA肌肉注射（1mg/剂量）。临床和免疫学随访至第64周或直至临床/放射学疾病进展。
DOM特异性免疫反应证明疫苗递送成功。所有无可测量疾病的患者与60%的晚期疾病患者有免疫反应，而分别有58%和20%的患者扩增了抗CAP - 1 CD8 T细胞。CAP - 1特异性T细胞仅在接种疫苗后在血液中可检测到，但也可在先前切除的癌组织中鉴定出来。48%的患者报告了胃肠道不良事件腹泻，与无腹泻的患者相比，腹泻与CEA更频繁下降（P < 0.001）以及更好的整体免疫反应[更大幅度（P < 0.001）、频率（P = 0.004）和持续时间的抗DOM反应]相关。在晚期疾病患者中，CEA下降与更好的总生存期相关（HR = 0.14，P = 0.017）。通过质谱法在正常肠黏膜和原发性结直肠癌组织的MHC I类上可检测到CAP - 1肽，这为通过CD8 T细胞攻击导致腹泻提供了一个机制解释。
我们的数据表明，DNA疫苗接种能够克服正常组织和肿瘤组织中的外周耐受，值得在联合研究中进行测试，例如，与抗PD1抗体治疗并行接种。临床癌症研究；22(19)；4827 - 36。©2016美国癌症研究协会。
