Intradermal Vaccinations With RNA Coding for TAA Generate CD8+ and CD4+ Immune Responses and Induce Clinical Benefit in Vaccinated Patients
Intradermal Vaccinations With RNA Coding for TAA Generate CD8+ and CD4+ Immune Responses and Induce Clinical Benefit in Vaccinated Patients
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DOI：
10.1038/mt.2010.289
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发表时间：
2011-05-01
影响因子：
12.4
通讯作者：
Brossart, Peter
中科院分区：
文献类型：
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作者：
Rittig, Susanne M.;Haentschel, Maik;Brossart, Peter
这项I/II期非随机试验的目的是评估使用粒细胞-巨噬细胞集落刺激因子（GM-CSF）作为佐剂在IV期肾细胞癌患者中进行基于mRNA的疫苗接种的可行性、安全性以及免疫和临床反应。皮内注射体外转录的裸mRNA，这是使用质粒编码的肿瘤相关抗原粘蛋白1（MUC 1），癌胚抗原（CEA），人表皮生长因子受体2（Her-2/neu），端粒酶，生存素，和黑色素瘤相关抗原1（MAGE-A1）进行30例入组患者。在前14名患者（组群A）中，在第0、14、28和42天接种疫苗（20 μ g/抗原），而在连续的16名患者（组群B）中，使用由在第0-3、7-10、28和42天注射（50 μ g/抗原）组成的强化方案。在两个队列中，在该诱导期后，每月重复接种疫苗，直至通过实体瘤缓解评价标准（RECIST）分析肿瘤进展。疫苗接种耐受性良好，无严重副作用并诱导临床应答[队列A中6例疾病稳定（SD）和1例部分应答，队列B中9例SD]。在队列A中，35.7%的患者存活4年（中位生存期24个月），而队列B中为31.25%（中位生存期29个月）。使用干扰素-γ（IFN-γ）酶联免疫吸附斑点（ELISpot）和Cr-释放试验，显示了几种肿瘤相关抗原（TAA）诱导的CD 4（+）和CD 8（+）T细胞应答。
The aim of this phase I/II nonrandomized trial was to assess feasibility, safety as well as immunological and clinical responses of a mRNA-based vaccination in patients with stage IV renal cell cancer using granulocyte-macrophage colony stimulating factor (GM-CSF) as adjuvant. Intradermal injections of in vitro transcribed naked mRNA, which was generated using plasmids coding for the tumor-associated antigens mucin 1(MUC1), carcinoembryonic (CEA), human epidermal growth factor receptor 2 (Her-2/neu), telomerase, survivin, and melanoma-associated antigen 1 (MAGE-A1) were performed in 30 enrolled patients. In the first 14 patients (cohort A) vaccinations were administered on days 0, 14, 28, and 42 (20 mu g/antigen) while in the consecutive 16 patients (cohort B) an intensified protocol consisting of injections at days 0-3, 7-10, 28, and 42 (50 mu g/antigen) was used. In both cohorts, after this induction period, vaccinations were repeated monthly until tumor progression analyzed by Response Evaluation Criteria In Solid Tumors criteria (RECIST). Vaccinations were well tolerated with no severe side effects and induced clinical responses [six stable diseases (SD) and one partial response in cohort A and nine SD in cohort B]. In cohort A, 35.7% survived 4 years (median survival 24 months) compared to 31.25% in cohort B (median survival 29 months). Induction of CD4(+) and CD8(+) T cell responses was shown for several tumor-associated antigens (TAA) using interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot (ELISpot) and Cr-release assays.