Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection.
Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection.
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DOI：
10.1186/s40425-017-0277-7
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发表时间：
2017-09-19
影响因子：
10.9
通讯作者：
Fisher K
中科院分区：
文献类型：
--
作者：
Garcia-Carbonero R;Salazar R;Duran I;Osman-Garcia I;Paz-Ares L;Bozada JM;Boni V;Blanc C;Seymour L;Beadle J;Alvis S;Champion B;Calvo E;Fisher K
Enadenotucirev（以前称为ColoAd 1）是一种具有临床前活性的肿瘤选择性嵌合腺病毒。该I期作用机制研究评估了enadenotucirev在可切除的结直肠癌（CRC）、非小细胞肺癌（NSCLC）、尿路上皮细胞癌（UCC）和肾细胞癌（RCC）患者中的静脉（IV）给药与对照物瘤内（IT）给药CRC患者队列。入选了17例计划进行原发性肿瘤切除术的患者。在第1天IT注射enadenotucirev（仅CRC）单次给药（≤ 3 × 1011病毒颗粒[vp]），然后在第8-15天切除。在第1、3和5天分别静脉输注enadenotucirev 3次（1 × 1012 vp），然后在第8-15天（CRC）或第10-25天（NSCLC、UCC和RCC）切除。使用核病毒六邻体的免疫组织化学染色和病毒基因组DNA的定量聚合酶链反应来测量Enadenotucirev活性。在IV输注后，在大多数肿瘤样品中观察到enadenotucirev的递送，在正常组织中几乎没有或没有可证实的活性。这种病毒递送（通过IV和IT给药）伴随着80%的测试肿瘤样品中的高局部CD 8+细胞浸润，表明潜在的致腺病毒驱动的免疫应答。两种enadenotucirev给药方法耐受性良好，没有治疗相关的严重不良事件。这项研究提供了关键的交付和可行性数据，以支持在一系列上皮肿瘤的临床试验中使用enadenotucirev或其治疗性转基因衍生物，包括正在进行的enadenotucirev与检查点抑制剂nivolumab的联合研究。它还提供了对enadenotucirev的潜在免疫刺激特性的见解。本MOA研究是一项I期、多中心、非随机、开放标签研究，旨在研究术前环境中enadenotucirev的给药情况（ClinicalTrials.gov：NCT 02053220）。本文的在线版本（doi：10.1186/s40425-017-0277-7）包含补充材料，可供授权用户使用。
Enadenotucirev (formerly ColoAd1) is a tumor-selective chimeric adenovirus with demonstrated preclinical activity. This phase 1 Mechanism of Action study assessed intravenous (IV) delivery of enadenotucirev in patients with resectable colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), urothelial cell cancer (UCC), and renal cell cancer (RCC) with a comparator intratumoral (IT) dosed CRC patient cohort. Seventeen patients scheduled for primary tumor resection were enrolled. IT injection of enadenotucirev (CRC only) was administered as a single dose (≤ 3 × 1011 viral particles [vp]) on day 1, followed by resection during days 8–15. IV infusion of enadenotucirev was administered by three separate doses (1 × 1012 vp) on days 1, 3, and 5, followed by resection during days 8–15 (CRC) or days 10–25 (NSCLC, UCC, and RCC). Enadenotucirev activity was measured using immunohistochemical staining of nuclear viral hexon and quantitative polymerase chain reaction for viral genomic DNA. Delivery of enadenotucirev was observed in most tumor samples following IV infusion, with little or no demonstrable activity in normal tissue. This virus delivery (by both IV and IT dosing) was accompanied by high local CD8+ cell infiltration in 80% of tested tumor samples, suggesting a potential enadenotucirev-driven immune response. Both methods of enadenotucirev delivery were well tolerated, with no treatment-associated serious adverse events. This study provides key delivery and feasibility data to support the use of IV infusion of enadenotucirev, or therapeutic transgene-bearing derivatives of it, in clinical trials across a range of epithelial tumors, including the ongoing combination study of enadenotucirev with the checkpoint inhibitor nivolumab. It also provides insights into the potential immune-stimulating properties of enadenotucirev. This MOA study was a phase 1, multicenter, non-randomized, open-label study to investigate the administration of enadenotucirev in a preoperative setting (ClinicalTrials.gov: NCT02053220). The online version of this article (doi:10.1186/s40425-017-0277-7) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/j.omto.2016.11.003
发表时间：
2017-03-17
期刊：
Molecular therapy oncolytics
影响因子：
--
作者：
Dyer A;Di Y;Calderon H;Illingworth S;Kueberuwa G;Tedcastle A;Jakeman P;Chia SL;Brown A;Silva MA;Barlow D;Beadle J;Hermiston T;Ferguson DJ;Champion B;Fisher KD;Seymour LW
通讯作者：
Seymour LW
影响因子：
3.6
作者：
Luo Y;Yu M;Grady WM
通讯作者：
Grady WM
影响因子：
2.2
作者：
Ferguson MS;Lemoine NR;Wang Y
通讯作者：
Wang Y
影响因子：
4.2
作者：
Doronin, Konstantin;Shashkova, Elena V.;Barry, Michael A.
通讯作者：
Barry, Michael A.
影响因子：
9.2
作者：
DONNADIEU, E;BISMUTH, C;TRAUTMANN, A
通讯作者：
TRAUTMANN, A