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首页> 外文期刊>Vaccine >An adenoviral cancer vaccine co-encoding a tumor associated antigen together with secreted 4-1BBL leads to delayed tumor progression
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An adenoviral cancer vaccine co-encoding a tumor associated antigen together with secreted 4-1BBL leads to delayed tumor progression

机译：共编码肿瘤相关抗原和分泌的4-1BBL的腺病毒疫苗导致肿瘤进展延迟

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Previous studies have shown promising results when using an agonistic anti-4-1BB antibody treatment against established tumors. While this is promising, this type of treatment can induce severe side effects. Therefore, we decided to incorporate the membrane form of 4-1BB ligand (4-1BBL) in a replicative deficient adenovirus vaccine expressing the invariant chain (Ii) adjuvant fused to a tumor associated antigen (TAA). The Ii adjuvant increases and prolongs TAA specific CD8+ T cells as previously shown and local expression of 4-1BBL was chosen to avoid the toxicity associated with systemic antibody administration. Furthermore, adenovirus encoded 4-1BBL expression has previously been successfully used to enhance responses toward Plasmodium falciparum and Influenza A antigens. We showed that the incorporation of 4-1BBL in the adenovirus vector led to surface expression of 4-1BBL on antigen presenting cells, but it did not enhance T cell responses in mice towards the Ii linked antigen. In tumor-bearing mice, our vaccine was found to decrease the frequency of TAA specific CD8+ T cells, but this difference did not alter the therapeutic efficacy. In order to reconcile our findings with the previous reports of increased anti-cancer efficacy using systemically delivered 4-1BB agonists, we incorporated a secreted version of 4-1BBL (Fc-4-1BBL) in our vaccine and co-expressed it with the Ii linked to TAA. In tumor bearing mice, this vaccine initially delayed tumor growth and slightly increased survival compared to the vaccine expressing the membrane form of 4-1BBL Accordingly, secreted 4-1BBL co-encoded with the Ii linked antigen may offer a simplification compared to administration of drug and vaccine separately. (C) 2016 Elsevier Ltd. All rights reserved.
机译：以前的研究表明，当针对已建立的肿瘤使用激动性抗4-1BB抗体治疗时，结果令人鼓舞。尽管这是有希望的，但是这种类型的治疗会引起严重的副作用。因此，我们决定将4-1BB配体（4-1BBL）的膜形式并入复制性缺陷型腺病毒疫苗中，该疫苗表达与肿瘤相关抗原（TAA）融合的不变链（Ii）佐剂。如先前所示，II佐剂增加并延长TAA特异性CD8 + T细胞，并选择4-1BBL的局部表达以避免与全身性抗体施用相关的毒性。此外，先前已成功地使用编码4-1BBL表达的腺病毒来增强对恶性疟原虫和A型流感抗原的应答。我们表明，在腺病毒载体中掺入4-1BBL导致抗原提呈细胞上4-1BBL的表面表达，但并没有增强小鼠对Ii连接抗原的T细胞应答。在荷瘤小鼠中，发现我们的疫苗可降低TAA特异性CD8 + T细胞的频率，但这种差异不会改变治疗效果。为了使我们的发现与以前使用全身递送的4-1BB激动剂提高抗癌效力的报道相一致，我们在疫苗中掺入了4-1BBL（Fc-4-1BBL）的分泌形式，并与它共同表达。 ii链接到TAA。在荷瘤小鼠中，与表达4-1BBL膜形式的疫苗相比，该疫苗最初延迟了肿瘤的生长，并略微提高了存活率。因此，与Ii连接抗原共同编码的分泌4-1BBL与给药相比可以简化和疫苗分开。 （C）2016 Elsevier Ltd.保留所有权利。

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