CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model
CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model
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DOI：
10.4049/jimmunol.170.6.3401
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发表时间：
2003-03-15
影响因子：
4.4
通讯作者：
Ellenhorn, JDI
中科院分区：
文献类型：
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作者：
Espenschied, J;Lamont, J;Ellenhorn, JDI
p53在所有癌症中有一半过表达，并且是免疫疗法的疫苗方法的有吸引力的靶标。p53过表达通常是点突变的结果，点突变使大部分蛋白质处于其野生型形式。因此，大多数p53序列是野生型的，使其成为自身蛋白，耐受性在限制免疫应答中起作用。为了克服对p53的耐受性，我们已经在非致病性减毒痘病毒、修饰的安卡拉牛痘病毒（表达野生型鼠p53的重组修饰的安卡拉牛痘病毒（rMVAp 53））中表达了野生型鼠p53。用rMVAp 53疫苗免疫的小鼠产生强烈的p53特异性CTL应答。评价rMVAp 53疫苗抑制过表达突变型p53的同基因鼠肉瘤Meth A生长的能力。将小鼠接种致死剂量（s.c.的Meth A肿瘤细胞，并在3天后通过腹膜内注射接种5 × 10（7）PFU的rMVAp 53。大多数小鼠保持无肿瘤并且对Meth A肿瘤细胞的再激发具有抗性。我们希望确定rMVAp 53免疫是否可以影响对已建立的、可触知的Meth A肿瘤的排斥。在随后的实验中，给小鼠注射10（6）个Meth A肿瘤细胞，6天后用抗CTLA-4 Ab（9 H10）和rMVAp 53处理。大多数治疗的小鼠具有完全的肿瘤消退沿着持久的肿瘤免疫。体内Ab消耗证实，抗肿瘤作用主要是CD 8依赖性的，在较小程度上是CD 4依赖性的。这些实验证明了在恶性肿瘤中靶向p53的新型无细胞疫苗的潜力。
p53 is overexpressed by half of all cancers, and is an attractive target for a vaccine approach to immunotherapy. p53 overexpression is frequently the result of point mutations, which leaves the majority of the protein in its wild-type form. Therefore, the majority of p53 sequence is wild type, making it a self-protein for which tolerance plays a role in limiting immune responses. To overcome tolerance to p53, we have expressed wild-type murine p53 in the nonpathogenic attenuated poxvirus, modified vaccinia virus Ankara (recombinant modified vaccinia virus Ankara expressing wild-type murine p53 (rMVAp53)). Mice immunized with rMVAp53 vaccine developed vigorous p53-specific CTL responses. rMVAp53 vaccine was evaluated for its ability to inhibit the outgrowth of the syngeneic murine sarcoma Meth A, which overexpresses mutant p53. Mice were inoculated with a lethal dose (5 X 10(5) cells injected s.c.) of Meth A tumor cells and vaccinated by i.p. injection 3 days later with 5 X 10(7) PFU of rMVAp53. The majority of mice remained tumor free and resistant to rechallenge with Meth A tumor cells. We wished to determine whether rMVAp53 immunization could effect the rejection of an established, palpable Meth A tumor. In subsequent experiments, mice were injected with 10(6) Meth A tumor cells, and treated 6 days later with anti-CTLA-4 Ab (9H10) and rMVAp53. The majority of treated mice had complete tumor regression along with lasting tumor immunity. In vivo Ab depletion confirmed that the antitumor effect was primarily CD8 and to a lesser extent CD4 dependent. These experiments demonstrate the potential of a novel cell-free vaccine targeting p53 in malignancy.