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Immunization with a Plasmid DNA Vaccine Encoding the N-Terminus of Insulin-like Growth Factor Binding Protein-2 in Advanced Ovarian Cancer Leads to High-level Type I Immune Responses
Clinical Cancer Research ( IF 11.5 ) Pub Date : 2021-12-01 , DOI: 10.1158/1078-0432.ccr-21-1579
Denise L Cecil 1 , John B Liao 1 , Yushe Dang 1 , Andrew L Coveler 1 , Angela Kask 1 , Yi Yang 1 , Jennifer S Childs 1 , Doreen M Higgins 1 , Mary L Disis 1
Affiliation  

Purpose: Cancer vaccines targeting nonmutated proteins elicit limited type I T-cell responses and can generate regulatory and type II T cells. Class II epitopes that selectively elicit type I or type II cytokines can be identified in nonmutated cancer-associated proteins. In mice, a T-helper I (Th1) selective insulin-like growth factor binding protein-2 (IGFBP-2) N-terminus vaccine generated high levels of IFNγ secreting T cells, no regulatory T cells, and significant antitumor activity. We conducted a phase I trial of T-helper 1 selective IGFBP-2 vaccination in patients with advanced ovarian cancer. Patients and Methods: Twenty-five patients were enrolled. The IGFBP-2 N-terminus plasmid-based vaccine was administered monthly for 3 months. Toxicity was graded by NCI criteria and antigen-specific T cells measured by IFNγ/IL10 ELISPOT. T-cell diversity and phenotype were assessed. Results: The vaccine was well tolerated, with 99% of adverse events graded 1 or 2, and generated high levels of IGFBP-2 IFNγ secreting T cells in 50% of patients. Both Tbet+ CD4 ( P = 0.04) and CD8 ( P = 0.007) T cells were significantly increased in immunized patients. There was no increase in GATA3+ CD4 or CD8, IGFBP-2 IL10 secreting T cells, or regulatory T cells. A significant increase in T-cell clonality occurred in immunized patients ( P = 0.03, pre- vs. post-vaccine) and studies showed the majority of patients developed epitope spreading within IGFBP-2 and/or to other antigens. Vaccine nonresponders were more likely to have preexistent IGFBP-2 specific immunity and demonstrated defects in CD4 T cells, upregulation of PD-1, and downregulation of genes associated with T-cell activation, after immunization. Conclusions: IGFBP-2 N-terminus Th1 selective vaccination safely induces type I T cells without evidence of regulatory responses.

中文翻译:

在晚期卵巢癌中用编码胰岛素样生长因子结合蛋白-2 N 末端的质粒 DNA 疫苗进行免疫导致高水平的 I 型免疫反应

目的:针对非突变蛋白质的癌症疫苗引发有限的 I 型 T 细胞反应,并能产生调节性和 II 型 T 细胞。可以在非突变的癌症相关蛋白中鉴定选择性引发 I 型或 II 型细胞因子的 II 类表位。在小鼠中,T-helper I (Th1) 选择性胰岛素样生长因子结合蛋白-2 (IGFBP-2) N 末端疫苗产生高水平的分泌 IFNγ 的 T 细胞,没有调节性 T 细胞,并且具有显着的抗肿瘤活性。我们对晚期卵巢癌患者进行了 T-helper 1 选择性 IGFBP-2 疫苗的 I 期试验。患者和方法:招募了 25 名患者。基于 IGFBP-2 N 末端质粒的疫苗每月接种一次,持续 3 个月。毒性通过 NCI 标准分级,抗原特异性 T 细胞通过 IFNγ/IL10 ELISPOT 测量。评估了 T 细胞多样性和表型。结果:疫苗耐受性良好,99% 的不良事件为 1 或 2 级,50% 的患者产生高水平的 IGFBP-2 IFNγ 分泌 T 细胞。Tbet+ CD4 (P = 0.04) 和 CD8 (P = 0.007) T 细胞在免疫患者中均显着增加。GATA3+ CD4 或 CD8、IGFBP-2 IL10 分泌 T 细胞或调节性 T 细胞没有增加。免疫患者中 T 细胞克隆性显着增加(P = 0.03,疫苗接种前与疫苗接种后),研究表明大多数患者在 IGFBP-2 和/或其他抗原中出现表位扩散。疫苗无反应者更有可能具有预先存在的 IGFBP-2 特异性免疫,并表现出 CD4 T 细胞缺陷、PD-1 上调和与 T 细胞激活相关的基因下调,免疫后。结论:IGFBP-2 N-末端 Th1 选择性疫苗接种安全地诱导 IT 型细胞,而没有调节反应的证据。
更新日期:2021-12-01
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