IL-12p70-producing patient DC vaccine elicits Tc1-polarized immunity
IL-12p70-producing patient DC vaccine elicits Tc1-polarized immunity
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DOI：
10.1172/jci68395
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发表时间：
2013-08-01
影响因子：
15.9
通讯作者：
Linette, Gerald P.
中科院分区：
文献类型：
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作者：
Carreno, Beatriz M.;Becker-Hapak, Michelle;Linette, Gerald P.
背景IL-12 p70的全身给药已在癌症患者中证明了临床活性，但剂量限制性毒性阻碍了其在疫苗制剂中的掺入。在这里，我们报告了免疫和临床结果后，接种CD 40 L/IFN-γ成熟，IL-12 p70生产的DC。7名HLA-A*0201（+）新诊断的IV期黑素瘤患者使用自体肽脉冲的、CD 40 L/IFN-γ成熟的DC针对gp 100黑素瘤抗原进行免疫。每周采集PBMC，通过四聚体分析和功能测定进行免疫监测。在基线、第9周和第18周进行CT成像，使用RECIST进行临床评估。7例治疗患者中有6例对所有3种黑色素瘤gp 100抗原衍生肽产生持续的T细胞免疫。6例免疫应答者中有3例出现了确认的临床应答（1例完全缓解>4年，2例部分应答）。重要的是，DC疫苗衍生的IL-12 p70水平与进展时间正相关（P = 0.019，对数秩），正如通过IFN-γ/IL-13和IFN-γ/IL-5比率评估的T细胞毒性1（Tc 1）免疫一样（分别为P = 0.035和P = 0.030，对数秩）。相比之下，在临床无应答患者DC中，在CD 40 L/IFN-γ活化后鉴定出IL-12 p35转录的途径特异性缺陷，并且来自这些患者的gp 100特异性T细胞显示Tc 2表型。将TLR 3和TLR 8激动剂结合到CD 40 L/IFN-γ活化方案中纠正了来自临床无应答患者的DC中IL-12 p70产生缺陷。这些发现强调了IL-12 p70在癌症患者中治疗性1型抗原特异性CD 8（+）T细胞免疫的发展中的重要作用。
Background. 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-gamma-matured, IL-12p70-producing DCs.Methods. 7 HLA-A*0201(+) newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-gamma-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.Results. 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-gamma/IL-13 and IFN-gamma/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-gamma 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-gamma activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients.Conclusion. 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.