Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
J Immunother Cancer. 2021 Apr;9(4). doi: 10.1136/jitc-2020-002224.
OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express granulocyte-macrophage colony-stimulating factor to enhance antitumor immune responses. We investigated the safety, tolerability and antitumor activity of OH2 as single agent or in combination with HX008, an anti-programmed cell death protein 1 antibody, in patients with advanced solid tumors.
In this multicenter, phase I/II trial, we enrolled patients with standard treatment-refractory advanced solid tumors who have injectable lesions. In phase I, patients received intratumoral injection of OH2 at escalating doses (10, 10 and 10CCID50/mL) as single agent or with fixed-dose HX008. The recommended doses were then expanded in phase II. Primary endpoints were safety and tolerability defined by the maximum-tolerated dose and dose-limiting toxicities (DLTs) in phase I, and antitumor activity assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase II.
Between April 17, 2019 and September 22, 2020, 54 patients with metastatic cancers were enrolled. Forty patients were treated with single agent OH2, and 14 with OH2 plus HX008. No DLTs were reported with single agent OH2 in phase I. Four patients, having metastatic mismatch repair-proficient rectal cancer or metastatic esophageal cancer, achieved immune-partial response, with two from the single agent cohort and two from the combination cohort. The duration of response were 11.25+ and 14.03+ months for the two responders treated with single agent OH2, and 1.38+ and 2.56+ months for the two responders in the combination cohort. The most common treatment-related adverse event (TRAE) with single agent OH2 was fever (n=18, 45.0%). All TRAEs were of grade 1-2, except one case of grade 3 fever in the 10CCID50/mL group. No treatment-related serious AEs occurred. Single agent OH2 induced alterations in the tumor microenvironment, with clear increases in CD3 and CD8 cell density and programmed death-ligand 1 expression in the patients' post-treatment biopsies relative to baseline.
Intratumoral injection of OH2 was well-tolerated, and demonstrated durable antitumor activity in patients with metastatic esophageal and rectal cancer. Further clinical development of OH2 as single agent or with immune checkpoint inhibitors in selected tumor types is warranted.
OH2 是一种经过基因工程改造的单纯疱疹病毒 2 型溶瘤病毒，旨在选择性地在肿瘤细胞中扩增，并表达粒细胞-巨噬细胞集落刺激因子，以增强抗肿瘤免疫反应。我们研究了 OH2 作为单一药物或与 HX008（一种抗程序性死亡蛋白 1 抗体）联合用于晚期实体瘤患者的安全性、耐受性和抗肿瘤活性。
在这项多中心、I/II 期试验中，我们招募了标准治疗耐药的晚期实体瘤患者，这些患者有可注射的病灶。在 I 期，患者接受递增剂量（10、10 和 10CCID50/mL）的 OH2 瘤内注射，作为单一药物或与固定剂量 HX008 联合使用。然后在 II 期扩大了推荐剂量。主要终点是 I 期最大耐受剂量和剂量限制性毒性（DLTs）定义的安全性和耐受性，以及根据实体瘤反应评估标准（RECIST 版本 1.1）和免疫 RECIST 在 II 期评估的抗肿瘤活性。
2019 年 4 月 17 日至 2020 年 9 月 22 日，共招募了 54 名转移性癌症患者。40 名患者接受了 OH2 单一药物治疗，14 名患者接受了 OH2 联合 HX008 治疗。I 期 OH2 单药治疗未报告 DLTs。四名患有转移性错配修复功能正常的直肠癌或转移性食管癌的患者达到了免疫部分缓解，其中两名来自单一药物队列，两名来自联合队列。两名接受 OH2 单一药物治疗的应答者的缓解持续时间分别为 11.25+和 14.03+个月，而联合队列中的两名应答者的缓解持续时间分别为 1.38+和 2.56+个月。OH2 单一药物治疗最常见的治疗相关不良事件（TRAE）是发热（n=18，45.0%）。所有 TRAE 均为 1-2 级，除 10CCID50/mL 组有 1 例 3 级发热外。无治疗相关严重不良事件发生。OH2 单一药物治疗诱导肿瘤微环境发生改变，与基线相比，患者治疗后活检中 CD3 和 CD8 细胞密度和程序性死亡配体 1 表达明显增加。
OH2 瘤内注射耐受性良好，在转移性直肠癌和食管癌患者中显示出持久的抗肿瘤活性。在选定的肿瘤类型中，进一步开发 OH2 作为单一药物或与免疫检查点抑制剂联合使用是有必要的。
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