Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer.
Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer.
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在晚期结直肠癌中，对剂量，安全性，免疫原性和总体生存的1/2期试验进行了扩展评估。
DOI：
10.1007/s00262-015-1706-4
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Jones FR
中科院分区：
文献类型：
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作者：
Balint JP;Gabitzsch ES;Rice A;Latchman Y;Xu Y;Messerschmidt GL;Chaudhry A;Morse MA;Jones FR
进行了一项1/2期临床试验，评估了用先进一代Ad 5 [E1-，E2 b-]-CEA（6D）疫苗免疫治疗后转移性结直肠癌（mCRC）患者的剂量、安全性、免疫原性和总生存期。我们报告了我们对长期总生存率的扩展观察和对治疗患者亚组的进一步免疫分析，包括评估溶细胞T细胞应答、T调节细胞（Treg）与T效应细胞（Teff）的比率、外周血单核细胞（PBMC）的流式细胞术和HLA-A2状态的测定。在长期随访期间观察到总生存率为20%（中位生存期为11个月），未报告长期不良反应。无论患者是否HLA-A2阳性或Ad 5免疫，免疫后细胞溶解性T细胞应答增加，细胞介导的免疫（CMI）应答被诱导。来自一小部分患者的PBMC样品可用于后续免疫分析。据观察，癌胚抗原（CEA）特异性CMI活性的水平下降，从他们的峰值在随访期间的5例分析。初步结果显示，在免疫后样品中检测到活化的CD 4+和CD 8 + T细胞，其表现出高CMI活性。评估Treg与Teff细胞比率，并且来自5名患者中的3名的样品在治疗方案期间表现出Treg与Teff细胞比率的降低。基于获得的有利的安全性和免疫原性数据，我们计划对将入组随机/对照临床试验的mCRC患者进行广泛的免疫学和生存分析，该临床试验研究Ad 5 [E1-，E2 b-]-CEA（6D）作为单药与加强免疫。
A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T-regulatory (Treg) to T-effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMC), and determination of HLA-A2 status. An overall survival of 20% (median survival of 11 months) was observed during long-term follow-up and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA) specific CMI activity decreased from their peak values during follow-up in 5 patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed and samples from 3 of 5 patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations.