单次静脉注射溶瘤腺病毒 TILT-123 可导致晚期实体瘤患者全身肿瘤转导和免疫应答。
Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors.
机构信息
Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.
TILT Biotherapeutics Ltd, Helsinki, Finland.
出版信息
J Exp Clin Cancer Res. 2024 Nov 6;43(1):297. doi: 10.1186/s13046-024-03219-0.
BACKGROUND
A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It is armed with tumor necrosis alpha and interleukin-2 for promoting T-cell activation and lymphocyte trafficking to tumors, thereby enhancing the antitumor immune response. Here, we present the findings after a single i.v. administration of TILT-123 in three phase I dose escalation clinical trials.
METHODS
Patients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 10 to 4 × 10 viral particles (VP). Blood was collected at baseline, 1, 16, and 192 h (7 days) post-treatment for bioavailability and serum analysis. Tumor biopsies were collected prior to treatment and 7 days post-treatment for analysis of viral presence and immunological effects. Patients did not receive any other cancer therapies during this period.
RESULTS
Across all three trials (TUNIMO, TUNINTIL, and PROTA), 52 total patients were treated with i.v. TILT-123. Overall, TILT-123 was found to be well-tolerated, with no dose-limiting toxicities observed. Post-treatment tumor biopsies showed expression of viral genes, presence of TILT-123 adenovirus proteins or DNA, and changes in immune cell infiltration from baseline. Increased virus dose did not lead to increased virus detection in tumors. Median overall survival was longer in patients with confirmed presence of TILT-123 in post-treatment biopsies (280 versus 190 days, p = 0.0405).
CONCLUSION
TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation.
TRIAL REGISTRATIONS
TUNIMO-NCT04695327. Registered 4 January 2021, https://clinicaltrials.gov/study/NCT04695327 . TUNINTIL-NCT04217473. Registered 19 December 2019, https://clinicaltrials.gov/study/NCT04217473 . PROTA-NCT05271318. Registered 4 February 2022, https://clinicaltrials.gov/study/NCT05271318 .
背景
已批准的溶瘤病毒的一个局限性是需要进行肿瘤内（i.t.）注射。TILT-123（igrelimogene litadenorepvec，Ad5/3-E2F-D24-hTNFα-IRES-hIL-2）是一种嵌合溶瘤腺病毒，由于其衣壳修饰和双重选择性装置，适合静脉内（i.v.）给药。它携带肿瘤坏死因子α和白细胞介素 2，以促进 T 细胞激活和淋巴细胞向肿瘤转移，从而增强抗肿瘤免疫反应。在这里，我们介绍了在三项 I 期剂量递增临床试验中单次静脉注射 TILT-123 后的发现。
方法
患有晚期实体瘤的患者最初接受了单次静脉注射剂量为 3×10 至 4×10 病毒粒子（VP）的 TILT-123。在治疗前和治疗后 7 天（192 小时，7 天）时采集血液以进行生物利用度和血清分析。在治疗前和治疗后 7 天采集肿瘤活检以分析病毒存在和免疫效应。在此期间，患者未接受任何其他癌症治疗。
结果
在所有三项试验（TUNIMO、TUNINTIL 和 PROTA）中，52 名患者接受了静脉注射 TILT-123 治疗。总体而言，TILT-123 耐受性良好，未观察到剂量限制性毒性。治疗后肿瘤活检显示病毒基因表达、TILT-123 腺病毒蛋白或 DNA 的存在以及免疫细胞浸润与基线相比的变化。增加病毒剂量不会导致肿瘤中病毒检测增加。在治疗后活检中证实存在 TILT-123 的患者的中位总生存期更长（280 天与 190 天，p=0.0405）。
结论
单次静脉注射 TILT-123 后表现出安全性和显著的肿瘤内免疫调节作用，值得进一步研究。
试验注册
TUNIMO-NCT04695327。2021 年 1 月 4 日注册，https://clinicaltrials.gov/study/NCT04695327。TUNINTIL-NCT04217473。2019 年 12 月 19 日注册，https://clinicaltrials.gov/study/NCT04217473。PROTA-NCT05271318。2022 年 2 月 4 日注册，https://clinicaltrials.gov/study/NCT05271318。
Zotero 插件