Sulaiman Raed, Aske Jennifer C, Espaillat Luis Rojas, Lin Xiaoqian, Starks David, Dale Adam, Gaster Kris, De Pradip, Dey Nandini
Avera McKennan Sioux Falls, SD, USA.
Avera Cancer Institute Sioux Falls, SD, USA.
Am J Cancer Res. 2024 Jun 15;14(6):3083-3103. doi: 10.62347/HTVU4235. eCollection 2024.
A scientific interrogation-driven approach to the clinical management of cancer patients is based on molecular profiling of the tumor. Empowered by the knowledge of oncogenic drivers and biomarkers, oncologists chart an optimal treatment path toward increasing the mathematical probability of a positive outcome. In this entire chain of events, an experimental proof of logical interrogation has never been incorporated before. Here, we provide the first evidence that the result of ex vivo testing of a drug matched to the genomic profiling of an N-of-1 tumor can deliver meaningful insight connecting scientific interrogation and a clinical event. Using resected tissues from endometrial (EC) and ovarian (OC) cancer patients, we designed a personalized ex vivo platform to test combinations of drugs in the default histological architecture of the individual tumors. Following the CART-T cells' principle, we co-cultured with autologous T-cells to test targeted drugs and immune checkpoint inhibitors. The study was designed with a limited clinical information window from patient registration/consent to obtaining the tumor tissues, and adjuvant treatment/post-surgery event (PSE) data were accessed retrospectively. Using a checkerboard analysis, we found that PSE-free survival time was longer in patients whose therapy "matched" the effective drug combination in ex vivo culture/co-cultures compared to those with no effect. Specifically, out of 32 EC patients in the "test & treatment-matched" category whose tumor cells failed to respond to ex vivo drug testing, none achieved > 4 and > 3 years of PSE-free survival. In contrast, out of 38 EC patients in the "test & treatment-matched" category, 4 and 6 patients, whose tumor cells responded to drugs in ex vivo culture, achieved > 4 and > 3 years of PSE-free survival, respectively. Cases with genomically-guided ex vivo testing showed that a "match" between an effective ex vivo drug combination and therapy resulted in late PSE, whereas a "match" between prescribed treatment and an ineffective drug combination in ex vivo testing led to early PSE. Our study demonstrates that integrating genomic data with personalized drug testing on an ex vivo culture/co-culture platform is an in gynecological cancers. This approach bridges the gap between next-generation drug testing in translational research and patient care, providing insight for improved treatment outcomes.
一种基于肿瘤分子图谱的以科学探究驱动的癌症患者临床管理方法。在致癌驱动因素和生物标志物知识的支持下，肿瘤学家绘制出一条最佳治疗路径，以提高获得积极结果的数学概率。在这一整个事件链中，此前从未纳入过逻辑探究的实验证据。在此，我们提供了首个证据，即针对1例肿瘤进行的与基因组图谱匹配的药物体外测试结果，能够提供将科学探究与临床事件联系起来的有意义见解。利用子宫内膜癌（EC）和卵巢癌（OC）患者的切除组织，我们设计了一个个性化的体外平台，在单个肿瘤的默认组织学结构中测试药物组合。遵循嵌合抗原受体T细胞（CART-T细胞）的原理，我们与自体T细胞共培养以测试靶向药物和免疫检查点抑制剂。该研究设计的临床信息窗口有限，从患者登记/同意到获取肿瘤组织，辅助治疗/手术后事件（PSE）数据是回顾性获取的。通过棋盘分析，我们发现与体外培养/共培养中有效药物组合“匹配”治疗的患者，其无PSE生存期比无效果的患者更长。具体而言，在“测试与治疗匹配”组的32例EC患者中，其肿瘤细胞对体外药物测试无反应，无一例实现超过4年和3年的无PSE生存期。相比之下，在“测试与治疗匹配”组的38例EC患者中，分别有4例和6例肿瘤细胞在体外培养中对药物有反应的患者，实现了超过4年和3年的无PSE生存期。基因组引导的体外测试病例表明，体外有效药物组合与治疗之间的“匹配”导致PSE出现较晚，而体外测试中规定治疗与无效药物组合之间的“匹配”导致PSE出现较早。我们的研究表明，在体外培养/共培养平台上整合基因组数据与个性化药物测试在妇科癌症中是一种……。这种方法弥合了转化研究中下一代药物测试与患者护理之间的差距，为改善治疗结果提供了见解。 （原文最后一处“is an in gynecological cancers”表述不完整，翻译时保留原文形式）
