O-OGC07 Endoscopically derived oesophageal adenocarcinoma organoids to assess potential response to neo-adjuvant therapy and virotherapy
O-OGC07 Endoscopically derived oesophageal adenocarcinoma organoids to assess potential response to neo-adjuvant therapy and virotherapy
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O-OGC07 内窥镜衍生的食管腺癌类器官，用于评估对新辅助治疗和病毒治疗的潜在反应
DOI：
10.1093/bjs/znab429.039
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发表时间：
2021
影响因子：
9.6
通讯作者：
Rayner C
中科院分区：
文献类型：
--
作者：
Rayner C
类器官是一种保留其来源器官的结构和功能的3D模型。从个体标准内镜活检中培养食管腺癌类器官以评估对治疗的反应可能会极大地改变新辅助治疗模式，明确谁将从治疗中受益，包括新的治疗方法。免疫检查点阻断（ICB）已被证明对食管腺癌有效。溶瘤病毒联合ICB可通过选择性感染肿瘤细胞并伴有免疫原性细胞死亡、释放新肿瘤抗原和改变肿瘤微环境来增强ICB的单独作用。方法本研究使用内镜活检获得的类器官来评估溶瘤性单纯疱疹病毒治疗食管腺癌的可行性。使用标准活检钳在分期内镜检查时取样。组织标本在条件培养基中悬浮于Matrigel之前，使用Miltenyi肿瘤解离试剂盒解离。每48小时更换一次培养基，每7-10天拆分一次穹顶。6代后，类器官与缺乏ICP 34.5和47的溶瘤性单纯疱疹病毒孵育。使用Incucyte SX5活细胞分析系统监测生长，并测量绿色荧光蛋白表达。结果成功建立并培养了食管腺癌患者的类器官6代以上。与未处理的类器官相比，用溶瘤性单纯疱疹病毒孵育的类器官生长明显减少，绿色荧光蛋白的表达增加，表明病毒感染。结论：我们已经证明了一种成功的方法来培养内镜活检的食管腺癌类器官。进一步确定患者对围手术期标准化疗的反应将有助于评估其未来提供定制治疗的潜力。溶瘤性单纯疱疹病毒能够感染并引起OAC类器官的裂解，支持其在驱动炎症性肿瘤微环境增加方面的潜在用途，该微环境可与免疫检查点阻断联合使用，以诱导患者的持久反应。
BackgroundOrganoids are 3D models that retain the architecture and function of the organ from which they are derived. Culture of oesophageal adenocarcinoma organoids from individual’s standard endoscopic biopsies to assess response to therapy could dramatically alter the neo-adjuvant treatment paradigm, giving clarity over who will benefit from therapy, including novel treatment methodologies. Immune checkpoint blockade (ICB) has been shown to be effective in oesophageal adenocarcinoma. Combining Oncolytic Virotherapy with ICB could enhance the action of ICB alone, through selective infection of tumour cells accompanied by immunogenic cell death, with release of neo-tumour antigens and alteration of the tumour microenvironment.MethodsThis study uses organoids derived from endoscopic biopsies to assess the viability of an oncolytic herpes simplex virus in the treatment of oesophageal adenocarcinoma. Samples were taken at staging endoscopy using standard biopsy forceps. Tissue specimens were dissociated using the Miltenyi tumour dissociation kit before being suspended in Matrigel in conditioned media. Media was changed every 48 hours with domes being split every 7-10 days. After >6 passages organoids were incubated with an oncolytic herpes simplex virus lacking ICP 34.5 and 47. Growth was monitored, and green fluorescence protein expression measured using the Incucyte SX5 Live Cell Analysis system.ResultsOrganoids were successfully established and cultured beyond 6 passages for patients with oesophageal adenocarcinoma. Organoids incubated with an oncolytic herpes simplex virus demonstrated significantly reduced growth compared to untreated organoids with increased expression of green fluorescence protein indicating viral infection.ConclusionsWe have demonstrated a successful methodology to culture Oesophageal adenocarcinoma organoids from endoscopic biopsies. Further work to determine their responses to standard chemotherapy used in the perioperative phase will help to assess their potential for providing bespoke therapy in the future. Oncolytic herpes simplex virus is able to infect and cause lysis of OAC organoids supporting its potential use in driving an increased inflammatory tumour microenvironment which could be combined with immune checkpoint blockade to induce durable responses for patients.