Biodistribution Analysis of Oncolytic Adenoviruses in Patient Autopsy Samples Reveals Vascular Transduction of Noninjected Tumors and Tissues
Biodistribution Analysis of Oncolytic Adenoviruses in Patient Autopsy Samples Reveals Vascular Transduction of Noninjected Tumors and Tissues
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DOI：
10.1038/mt.2015.125
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发表时间：
2015-10-01
影响因子：
12.4
通讯作者：
Hemminki, Akseli
中科院分区：
文献类型：
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作者：
Koski, Anniina;Bramante, Simona;Hemminki, Akseli
在溶瘤腺病毒的临床试验中，没有与治疗载体相关的死亡率。同样，在高级治疗准入计划（ATAP）中，290名患者接受了10种不同的病毒治疗，未观察到与媒介相关的死亡率。然而，由于在ATAP中接受腺病毒治疗的患者群体是经过大量预处理的患者，通常病情非常晚期，一些患者在接受病毒治疗后相对较快死亡，需要尸检以调查死因。进行了11次这样的尸检，并确认每个病例的死亡原因是疾病进展。调查先进治疗医疗产品安全性的监管要求为研究作为尸检常规部分收集的组织样本提供了独特的机会。溶瘤腺病毒DNA在广泛的组织中被发现，包括注射和非注射肿瘤以及各种正常组织，证明了载体通过血管途径传播的能力。此外，我们从静脉注射治疗患者的非注射脑转移瘤样本中恢复并培养了活病毒，证实溶瘤腺病毒可以通过血管内途径到达肿瘤。这里提出的数据提供了机制洞察的作用模式和溶瘤腺病毒在癌症患者的生物分布。
In clinical trials with oncolytic adenoviruses, there has been no mortality associated with treatment vectors. Likewise, in the Advanced Therapy Access Program (ATAP), where 290 patients were treated with 10 different viruses, no vector-related mortality was observed. However, as the patient population who received adenovirus treatments in ATAP represented heavily pretreated patients, often with very advanced disease, some patients died relatively soon after receiving their virus treatment mandating autopsy to investigate cause of death. Eleven such autopsies were performed and confirmed disease progression as the cause of death in each case. The regulatory requirement for investigating the safety of advanced therapy medical products presented a unique opportunity to study tissue samples collected as a routine part of the autopsies. Oncolytic adenoviral DNA was recovered in a wide range of tissues, including injected and noninjected tumors and various normal tissues, demonstrating the ability of the vector to disseminate through the vascular route. Furthermore, we recovered and cultured viable virus from samples of noninjected brain metastases of an intravenously treated patient, confirming that oncolytic adenovirus can reach tumors through the intravascular route. Data presented here give mechanistic insight into mode of action and biodistribution of oncolytic adenoviruses in cancer patients.