Alpha fetoprotein DNA prime and adenovirus boost immunization of two hepatocellular cancer patients.
Alpha fetoprotein DNA prime and adenovirus boost immunization of two hepatocellular cancer patients.
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DOI：
10.1186/1479-5876-12-86
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发表时间：
2014-04-05
影响因子：
7.4
通讯作者：
Geller DA
中科院分区：
文献类型：
--
作者：
Butterfield LH;Economou JS;Gamblin TC;Geller DA
甲胎蛋白（AFP）是一种在许多肝细胞癌（HCC）中过度表达的癌胚抗原。我们以前证明，HLA-A2限制性表位来自AFP的免疫原性在体外和体内，尽管高循环水平的这种癌胚抗原。为了测试能够激活肿瘤抗原特异性CD 8+和CD 4 + T细胞的更广泛适用的、不受HLA限制的、廉价的、无细胞的疫苗平台，我们在初免-加强疫苗策略中测试了质粒DNA构建体中的全长AFP与表达AFP的复制缺陷型腺病毒（AdV）的组合。筛选具有AFP+肿瘤和先前HCC治疗的HCC患者，并且两名患者接受了三次质粒DNA注射的疫苗接种，随后是单次AdV注射，所有均通过肌内（i.m.）递送。该疫苗耐受性良好且安全。两名患者均显示免疫证据。第一个病人有一个弱的AFP特异性T细胞反应，一个强的腺病毒特异性细胞反应和复发的AFP表达肝癌在9个月。第二例患者产生了强烈的AFP特异性CD 8+和CD 4+细胞应答以及AdV中和抗体应答，并在18个月时复发，血清AFP未增加。AFP DNA prime-AdV boost疫苗安全、免疫原性好。基线时循环中的抗AdV中和抗体并不阻止AFP特异性细胞免疫的发展。发展出CD 8+和CD 4 + AFP特异性T细胞免疫的患者具有更有利的无进展生存。这两名患者的观察结果支持在更大规模的临床试验中开发这种疫苗策略。ClinicalTrials.gov：NCT00093548
Alpha fetoprotein (AFP) is an oncofetal antigen over-expressed by many hepatocellular cancers (HCC). We previously demonstrated that HLA-A2-restricted epitopes derived from AFP are immunogenic in vitro and in vivo despite high circulating levels of this oncofetal antigen. In order to test a more broadly applicable, HLA-unrestricted, inexpensive, cell-free vaccine platform capable of activating tumor antigen-specific CD8+ and CD4+ T cells, we tested full length AFP in a plasmid DNA construct in combination with an AFP-expressing replication-deficient adenovirus (AdV) in a prime-boost vaccine strategy. HCC patients who had an AFP+ tumor and previous treatment for HCC were screened and two patients received vaccination with three plasmid DNA injections followed by a single AdV injection, all delivered intramuscularly (i.m.). The vaccine was well tolerated and safe. Both patients showed immunologic evidence of immunization. The first patient had a weak AFP-specific T cell response, a strong AdV-specific cellular response and recurred with an AFP-expressing HCC at nine months. The second patient developed a strong AFP-specific CD8+ and CD4+ cellular response and an AdV neutralizing antibody response, and recurred at 18 months without an increase in serum AFP. The AFP DNA prime-AdV boost vaccine was safe and immunogenic. Circulating anti-AdV neutralizing antibodies at baseline did not prohibit the development of AFP-specific cellular immunity. The patient who developed CD8+ and CD4+ AFP-specific T cell immunity had more favorable progression-free survival. The observations with these two patients support development of this vaccine strategy in a larger clinical trial. ClinicalTrials.gov: NCT00093548