Division of Surgical Oncology, Helen F. Graham Cancer Center and Research Institute, Christiana Care, Newark, Delaware, USA.
Gene Editing Institute, Helen F. Graham Cancer Center and Research Institute, Newark, Delaware, USA.
Hum Gene Ther. 2023 Apr;34(7-8):314-324. doi: 10.1089/hum.2022.228.
With efficient transduction across most cell types and larger packaging capacity, Adenovirus 5 (Ad5) makes an attractive choice as a viral vector. However, a reported past mortality and known immunogenicity cast doubt on the safety of its use. An online database search was performed for all clinical trials administering intratumoral injection of gene therapy packaged in Ad5, being conducted in the United States, and using the Common Terminology Criteria for Adverse Events (CTCAE). Studies with unclear adverse events (AE) were excluded. The primary outcome collected was grade ≥3 (AE). Analyses were performed using Fisher's exact test. Thirty-nine prospective clinical trials across a variety of cancers were identified: 14 studies of therapeutic Ad5 alone, 12 with chemotherapy, 16 with radiation, and 11 with surgery. There were 3 mortalities out of 756 patients (0.4%), which were most likely unrelated to Ad5: 1 due to hypoxic encephalopathy, 1 due to splenic vein thrombus, and 1 due to disease progression. In trials that reported total AE (grades 1-5), there were 284 (10.3%) grade ≥3 AE out of 2,745 total AE in 477 patients. The overall life-threatening (grade 4) AE rate was 1.4% (34/2,425 AE in 428 patients). Overall, the most frequent grade ≥3 AE were lymphopenia (20.6% in 14 trials, 209 patients), dyspnea (8.7% in 11 trials, 208 patients), and neutropenia (8.6% in 12 trials, 174 patients). The most frequent grade 4 AE were neutropenia (4.6%), lymphopenia (3.3%), and leukopenia (3.1% in 13 trials, 192 patients). Our analyses demonstrated relative overall safety of Ad5 and warrant re-evaluation for the use of Ad5 as a delivery vector for gene therapy products.
腺病毒 5（Ad5）能够高效转导大多数细胞类型，且包装容量较大，因此作为病毒载体极具吸引力。然而，其使用安全性受到过去报道的死亡率和已知的免疫原性的质疑。对在美国进行的、瘤内注射基因治疗载体为 Ad5 的所有临床试验进行了在线数据库检索，检索采用了不良事件常用术语标准（CTCAE）。对不良事件不明确的研究予以排除。主要收集的结果是≥3 级（AE）。采用 Fisher 确切概率法进行分析。共确定了 39 项不同癌症的前瞻性临床试验：单独使用治疗性 Ad5 的研究 14 项、化疗 12 项、放疗 16 项、手术 11 项。在 756 例患者中有 3 例死亡（0.4%），这很可能与 Ad5 无关：1 例由于缺氧性脑病，1 例由于脾静脉血栓形成，1 例由于疾病进展。在报告了所有不良事件（1-5 级）的试验中，477 例患者的 2745 例总不良事件中有 284 例（10.3%）≥3 级不良事件。危及生命的（4 级）不良事件总发生率为 1.4%（34/2425 例 AE，428 例患者）。总体而言，最常见的≥3 级不良事件为淋巴细胞减少症（14 项试验中有 20.6%，209 例患者）、呼吸困难（11 项试验中有 8.7%，208 例患者）和中性粒细胞减少症（12 项试验中有 8.6%，174 例患者）。最常见的 4 级不良事件为中性粒细胞减少症（4.6%）、淋巴细胞减少症（3.3%）和白细胞减少症（13 项试验中有 3.1%，192 例患者）。我们的分析表明 Ad5 总体相对安全，有必要重新评估 Ad5 作为基因治疗产品的递送载体的使用。
