Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Clin Invest. 2013 Aug;123(8):3383-94. doi: 10.1172/JCI68395. Epub 2013 Jul 11.
Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but dose-limiting toxicities have hindered its incorporation in vaccine formulations. Here, we report on the immunological and clinical outcomes upon vaccination with CD40L/IFN-γ-matured, IL-12p70-producing DCs.
7 HLA-A*0201+ newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-γ-matured DCs. PBMCs were taken weekly for immune monitoring by tetramer analysis and functional assays. CT imaging was performed at baseline, week 9, and week 18 for clinical assessment using RECIST.
6 of 7 treated patients developed sustained T cell immunity to all 3 melanoma gp100 antigen-derived peptides. 3 of the 6 immunological responders developed confirmed clinical responses (1 complete remission >4 years, 2 partial response). Importantly, DC vaccine-derived IL-12p70 levels positively correlated with time to progression (P = 0.019, log-rank), as did T-cytotoxic 1 (Tc1) immunity, as assessed by IFN-γ/IL-13 and IFN-γ/IL-5 ratios (P = 0.035 and P = 0.030, respectively, log-rank). In contrast, a pathway-specific defect in IL-12p35 transcription was identified upon CD40L/IFN-γ activation in clinical nonresponder patient DCs, and gp100-specific T cells from these patients displayed a Tc2 phenotype. Incorporation of TLR3 and TLR8 agonists into the CD40L/IFN-γ activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients.
These findings underscore the essential role of IL-12p70 in the development of therapeutic type 1 antigen-specific CD8+ T cell immunity in humans with cancer.
白细胞介素-12p70 的全身给药在癌症患者中显示出了临床活性，但剂量限制毒性阻碍了其在疫苗制剂中的应用。在这里，我们报告了用 CD40L/IFN-γ 成熟、IL-12p70 产生的树突状细胞（DC）进行疫苗接种后的免疫和临床结果。
7 名 HLA-A*0201+新诊断的 IV 期黑色素瘤患者使用自体肽脉冲、CD40L/IFN-γ 成熟的 DC 针对 gp100 黑色素瘤抗原进行免疫接种。每周采集 PBMC 进行免疫监测，通过四聚体分析和功能测定。使用 RECIST 进行基线、第 9 周和第 18 周的 CT 成像进行临床评估。
7 名治疗患者中的 6 名患者对所有 3 种黑色素瘤 gp100 抗原衍生肽产生了持续的 T 细胞免疫。6 名免疫应答者中有 3 名患者出现了确认的临床应答（1 例完全缓解>4 年，2 例部分缓解）。重要的是，DC 疫苗衍生的 IL-12p70 水平与无进展时间呈正相关（P=0.019，对数秩检验），Tc1 免疫也是如此，通过 IFN-γ/IL-13 和 IFN-γ/IL-5 比值评估（P=0.035 和 P=0.030，对数秩检验）。相比之下，在临床无应答者患者的 DC 中经 CD40L/IFN-γ 激活时，发现了 IL-12p35 转录的特异性缺陷，并且来自这些患者的 gp100 特异性 T 细胞显示出 Tc2 表型。在 CD40L/IFN-γ 激活方案中加入 TLR3 和 TLR8 激动剂纠正了来自临床无应答者患者的 DC 中的 IL-12p70 产生缺陷。
这些发现强调了白细胞介素-12p70 在癌症患者中产生治疗性 1 型抗原特异性 CD8+T 细胞免疫中的重要作用。
