肿瘤细胞治疗研究
英文原题：Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial.
TILT-123 治疗诱导效应淋巴细胞在肿瘤中积聚。外周淋巴细胞计数下降是评估溶瘤腺病毒治疗反应的一个有前景的生物标志物。
溶瘤病毒（OVs）是治疗免疫冷肿瘤的有前景的免疫治疗药物。然而，关于OVs在人体中的作用机制和临床相关生物标志物的研究仍然稀少。为了诱导针对实体瘤的强T细胞反应，开发了TILT-123（Ad5/3-E2F-d24-hTNFa-IRES-hIL2，igrelimogene litadenorepvec）。TILT-123编码两种转基因：肿瘤坏死因子α（TNFa）和白细胞介素-2（IL-2）。TUNIMO（NCT04695327）是一项在晚期实体瘤患者中使用TILT-123的I期临床试验，旨在评估TILT-123的安全性、疗效和免疫学效应。本研究通过使用研究期间从患者收集的生物样本，评估了TILT-123在TUNIMO试验中的免疫学效应，目的是利用这些发现开发可能的应答生物标志物，并深入了解可能的协同联合治疗。
20 例晚期实体瘤患者接受了 TILT-123 治疗。通过增强 CT 和氟脱氧葡萄糖正电子发射断层扫描评估治疗反应，并计算总生存期（OS）。以血液和肿瘤活检的形式收集患者的生物样本。收集的样本通过免疫组织化学、转录组学、蛋白质组学和流式细胞术进行分析。
TILT-123 诱导血液淋巴细胞计数呈周期性下降，且血液淋巴细胞计数下降幅度越大，与更好的影像学缓解和更长的 OS 相关。淋巴细胞计数结果在 96 例患者的外部对照数据集中得到验证。静脉注射 TILT-123 后，更显著的淋巴细胞计数变化与血浆蛋白质组中更强的免疫激活以及肿瘤中存在 TILT-123 mRNA 相关。关于其他检测。肿瘤活检分析显示，静脉注射 TILT-123 后 CD8+ T 细胞、CD4+ T 细胞和 NK 细胞数量增加，但瘤内注射 TILT-123 后未增加。静脉治疗和瘤内治疗后肿瘤中可见转录差异，从治疗中获益的患者在所有时间点均表现出更强的免疫激活下调。
BACKGROUND: Oncolytic viruses (OVs) are promising immunotherapeutics to treat immunologically cold tumors. However, research on the mechanism of action of OVs in humans and clinically relevant biomarkers is still sparse. To induce strong T-cell responses against solid tumors, TILT-123 (Ad5/3-E2F-d24-hTNFa-IRES-hIL2, igrelimogene litadenorepvec) was developed. TILT-123 encodes two transgenes: tumor necrosis alpha (TNFa) and interleukin-2 (IL-2). TUNIMO (NCT04695327) was a phase I clinical trial using TILT-123 in patients with advanced solid tumors aiming to assess the safety, efficacy, and immunological effects of TILT-123. Research presented in this study evaluated the immunological effects of TILT-123 in the TUNIMO trial by using biological samples collected from the patients during the study, with an objective to leverage the findings to develop possible biomarkers of response and gain insights into possible synergistic combination treatments. METHODS: 20 patients with advanced solid tumors were treated with TILT-123. Response to therapy was assessed with contrast-enhanced CT and fluorodeoxyglucose positron emission tomography, along with overall survival (OS) calculation. Biological samples from patients were collected in the form of blood and tumor biopsies. Collected samples were analyzed with immunohistochemistry, transcriptomics, proteomics, and flow cytometry. RESULTS: TILT-123 induced cyclical decreases in blood lymphocyte count, and more substantial blood lymphocyte count correlated with better radiographical response and longer OS. Lymphocyte count findings were confirmed with external control dataset of 96 patients. More substantial lymphocyte count change was linked to stronger immune activation in plasma proteome after intravenous TILT-123 and the presence of TILT-123 mRNA in tumors. Regarding other assays. tumor biopsies profiled showed increased amounts of CD8+ T cells, CD4+ T cells and NK cells after intravenous TILT-123, but not after intratumoral TILT-123. Transcriptional differences were seen in tumors after intravenous therapy and intratumoral therapy, with patients benefitting therapy showing stronger downregulation of immune activation at all time points. CONCLUSIONS: TILT-123 therapy induced accumulation of effector lymphocytes in tumors. Peripheral lymphocyte count decrease is a promising biomarker for assessing oncolytic adenovirus therapy response.
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