Effect of Preexisting Immunity on Oncolytic Adenovirus Vector INGN 007 Antitumor Efficacy in Immunocompetent and Immunosuppressed Syrian Hamsters
Effect of Preexisting Immunity on Oncolytic Adenovirus Vector INGN 007 Antitumor Efficacy in Immunocompetent and Immunosuppressed Syrian Hamsters
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DOI：
10.1128/jvi.02127-08
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发表时间：
2009-03-01
影响因子：
5.4
通讯作者：
Wold, William S. M.
中科院分区：
文献类型：
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作者：
Dhar, Debanjan;Spencer, Jacqueline F.;Wold, William S. M.
对腺病毒(Ad)载体的免疫应答可能是影响治疗效果的一个因素。为了探讨预先存在的免疫在瘤内注射Ad载体后的抗肿瘤效果中的作用以及载体在肿瘤到组织的扩散中的作用，我们采用了叙利亚仓鼠模型。这些动物具有免疫活性，它们的肿瘤和组织允许复制Ad5型(Ad5)。我们使用腺病毒死亡蛋白过表达Ad5为基础的载体INGN 007。皮下肿瘤是在接种或未接种Ad5的仓鼠中建立起来的。这些组中有一半的仓鼠用环磷酰胺进行免疫抑制。在所有组中，注射INGN 007的肿瘤生长明显慢于注射缓冲液的肿瘤。在免疫活性条件下，预先存在的免疫对载体抗肿瘤效果没有显著影响。注射载体后不久，幼龄仓鼠产生中和抗体(NAB)，幼虫组与免疫组之间的NAB滴度差异缩小。在免疫抑制条件下，预先存在的NAB确实显著降低了载体的效力。因此，NAB确实在一定程度上降低了载体的效力，但需要免疫抑制来观察其效果。在载体毒性方面，在免疫能力较强的幼龄仓鼠体内，载体从肿瘤向肝、肺溢出，而在免疫后的仓鼠体内，这种溢出几乎消除。因此，预先存在的对Ad5的免疫不会影响瘤内注射后INGN 007的抗肿瘤疗效，但免疫可以防止媒介从肿瘤溢出到肝脏和肺。
Immune responses against adenovirus (Ad) vectors pose a possible concern for the outcome of treatment efficacy. To address the role of preexisting immunity in oncolytic Ad vector antitumor efficacy following intratumoral injection of vector as well as tumor-to-tissue spread of the vector, we employed the Syrian hamster model. These animals are immunocompetent, and their tumors and tissues are permissive for replication of Ad type 5 (Ad5). We used the adenovirus death protein-overexpressing Ad5-based vector INGN 007. Subcutaneous tumors were established in groups of hamsters that were or were not immunized with Ad5. Half of the hamsters in these groups were immunosuppressed with cyclophosphamide. For all groups, tumors injected with INGN 007 grew significantly more slowly than those injected with buffer. Under immunocompetent conditions, there was no significant effect of preexisting immunity on vector antitumor efficacy. Soon after the tumors in naive animals were injected with vector, the hamsters developed neutralizing antibody (NAb) and the difference in NAb titers between the naive and immunized groups diminished. Under immunosuppressed conditions, preexisting NAb did significantly reduce vector efficacy. Thus, NAb do reduce vector efficacy to some extent, but immunosuppression is required to observe the effect. Regarding vector toxicity, there was spillover of vector from the tumor to the liver and lungs in naive immunocompetent hamsters, and this was nearly eliminated in the immunized hamsters. Thus, preexisting immunity to Ad5 does not affect INGN 007 antitumor efficacy following intratumoral injection, but immunity prevents vector spillover from the tumor to the liver and lungs.