Tocagen Inc., San Diego, California.
McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.
Clin Cancer Res. 2018 Oct 1;24(19):4680-4693. doi: 10.1158/1078-0432.CCR-18-0619. Epub 2018 Jun 26.
Toca 511 is a gammaretroviral replicating vector encoding cytosine deaminase that selectively infects tumor cells and converts the antifungal drug 5-fluorocytosine into the antineoplastic drug 5-fluorouracil, which directly kills tumor cells and stimulates antitumor immune responses. As part of clinical monitoring of phase I clinical trials in recurrent high-grade glioma, we have performed extensive molecular analyses of patient specimens to track vector fate. Toca 511 and Toca FC (extended-release 5-fluorocytosine) have been administered to 127 high-grade glioma patients across three phase I studies. We measured Toca 511 RNA and DNA levels in available body fluids and tumor samples from patients to assess tumor specificity. We mapped Toca 511 integration sites and sequenced integrated Toca 511 genomes from patient samples with detectable virus. We measured Toca 511 levels in a diverse set of tissue samples from one patient. Integrated Toca 511 is commonly detected in tumor samples and is only transiently detected in blood in a small fraction of patients. There was no believable evidence for clonal expansion of cells with integrated Toca 511 DNA, or preferential retrieval of integration sites near oncogenes. Toca 511 sequence profiles suggest most mutations are caused by APOBEC cytidine deaminases acting during reverse transcription. Tissue samples from a single whole-body autopsy affirm Toca 511 tumor selectivity. Toca 511 and Toca FC treatment was not associated with inappropriate integration sites and clonal expansion. The vector is tumor-selective and persistent in patients who received Toca 511 injections. .
托卡 511 是一种复制型γ逆转录病毒载体，可编码胞嘧啶脱氨酶，它选择性地感染肿瘤细胞，并将抗真菌药物 5-氟胞嘧啶转化为抗肿瘤药物 5-氟尿嘧啶，直接杀死肿瘤细胞并刺激抗肿瘤免疫反应。作为复发性高级别神经胶质瘤 I 期临床试验临床监测的一部分，我们对患者标本进行了广泛的分子分析，以追踪载体的命运。托卡 511 和托卡 FC（5-氟胞嘧啶延长释放制剂）已在三项 I 期研究中用于 127 名高级别神经胶质瘤患者。我们测量了患者可获得的体液和肿瘤标本中托卡 511 RNA 和 DNA 水平，以评估肿瘤的特异性。我们绘制了托卡 511 的整合位点，并对可检测到病毒的患者样本中的整合托卡 511 基因组进行了测序。我们测量了来自一名患者的一组不同组织样本中的托卡 511 水平。整合的托卡 511 通常在肿瘤样本中检测到，在一小部分患者的血液中短暂检测到。没有可信的证据表明整合了托卡 511 DNA 的细胞发生克隆扩增，也没有优先检索靠近癌基因的整合位点。托卡 511 序列谱表明，大多数突变是由 APOBEC 胞嘧啶脱氨酶在逆转录过程中引起的。来自单一全身尸检的组织样本证实了托卡 511 的肿瘤选择性。托卡 511 和托卡 FC 治疗与不合适的整合位点和克隆扩增无关。该载体在接受托卡 511 注射的患者中具有肿瘤选择性和持久性。
