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Intratumoral OH2, an Oncolytic Herpes Simplex Virus 2, in Patients with Advanced Solid Tumors: a Multicenter, Phase I/II Clinical Trial

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Intratumoral OH2, an Oncolytic Herpes Simplex Virus 2, in Patients with Advanced Solid Tumors: a Multicenter, Phase I/II Clinical Trial Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-002224 on 9 April 2021. Downloaded from Intratumoral OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: a multicenter, phase I/II clinical trial 1 1,2 1 3 4 5 Bo Zhang, Jing Huang , Jialin Tang, Sheng Hu, Suxia Luo, Zhiguo Luo, Fuxiang Zhou,6 Shiyun Tan,7 Jieer Ying,8 Qing Chang,9 Rui Zhang,9 Chengyun Geng,9 Dawei Wu,10 Xiangyong Gu,11 Binlei Liu11,12 To cite: Zhang B, Huang J, ABSTRACT with immune checkpoint inhibitors in selected tumor types Tang J, et al. Intratumoral Background OH2 is a genetically engineered oncolytic is warranted. OH2, an oncolytic herpes herpes simplex virus type 2 designed to selectively amplify simplex virus 2, in patients in tumor cells and express granulocyte- macrophage with advanced solid tumors: a colony- stimulating factor to enhance antitumor immune BACKGROUND multicenter, phase I/II clinical Oncolytic virotherapy represents a unique trial. Journal for ImmunoTherapy responses. We investigated the safety, tolerability and of Cancer 2021;9:e002224. antitumor activity of OH2 as single agent or in combination antitumor strategy using natural or geneti- doi:10.1136/jitc-2020-002224 with HX008, an anti- programmed cell death protein 1 cally engineered viruses to infect and repli- antibody, in patients with advanced solid tumors. cate in tumor cells. The mechanisms of the ► Additional supplemental Methods In this multicenter, phase I/II trial, we enrolled tumoricidal effect include direct tumor cell material is published online only. patients with standard treatment- refractory advanced solid lysis caused by selective infection, and the To view, please visit the journal tumors who have injectable lesions. In phase I, patients subsequent release of cell debris and viral online (http:// dx. doi. org/ 10. received intratumoral injection of OH2 at escalating doses antigens, which may overcome immunosup- 1136/ jitc- 2020- 002224). (106, 107 and 108CCID50/mL) as single agent or with fixed- dose HX008. The recommended doses were then pression in the tumor microenvironment Accepted 17 March 2021 expanded in phase II. Primary endpoints were safety and and trigger antitumor immune responses. In tolerability defined by the maximum- tolerated dose and addition, the advances in biotechnology have dose- limiting toxicities (DLTs) in phase I, and antitumor enabled the insertion of therapeutic trans- activity assessed per Response Evaluation Criteria in Solid genes into the viral genomes to enhance effi- http://jitc.bmj.com/ Tumors (RECIST version 1.1) and immune- RECIST in phase cacy.1 2 II. A diverse range of viruses have been studied Results Between April 17, 2019 and September 22, 2020, as candidates of oncolytic virus, among which 54 patients with metastatic cancers were enrolled. Forty the herpes simplex virus type 1 (HSV-1) was patients were treated with single agent OH2, and 14 with the earliest reported oncolytic viruses gener- OH2 plus HX008. No DLTs were reported with single agent 3 ated by genetic engineering. HSV derived on September 30, 2021 by guest. Protected copyright. OH2 in phase I. Four patients, having metastatic mismatch repair- proficient rectal cancer or metastatic esophageal oncolytic viruses may offer a few advantages, cancer, achieved immune- partial response, with two from including a broad host range allowing clin- the single agent cohort and two from the combination ical application in many different types of cohort. The duration of response were 11.25+ and 14.03+ cancers, the potential for incorporating a size- months for the two responders treated with single agent able foreign DNA, and the readily available OH2, and 1.38+ and 2.56+ months for the two responders antiherpetic therapy to control undesired in the combination cohort. The most common treatment- infection and replication.4 The significant related adverse event (TRAE) with single agent OH2 was benefits observed in the phase III random- © Author(s) (or their fever (n=18, 45.0%). All TRAEs were of grade 1–2, except ized trial of the HSV- based talimogene laher- 8 employer(s)) 2021. Re- use one case of grade 3 fever in the 10 CCID50/mL group. parepvec (T-VEC) in patients with advanced permitted under CC BY-NC. No No treatment- related serious AEs occurred. Single agent melanoma5 and its approval in the USA and commercial re- use. See rights OH2 induced alterations in the tumor microenvironment, and permissions. Published by European Union have shown great promise with clear increases in CD3+ and CD8+ cell density and BMJ. programmed death- ligand 1 expression in the patients’ for this class of anticancer agent and inspired For numbered affiliations see post- treatment biopsies relative to baseline. further advances in this field. end of article. Conclusions Intratumoral injection of OH2 was well- OH2 is a novel oncolytic virus derived Correspondence to tolerated, and demonstrated durable antitumor activity in from the wild-type HSV-2 strain HG52. In the Professor Jing Huang; patients with metastatic esophageal and rectal cancer. construction of this virus, the ICP34.5 neuro- huangjingwg@ 163. com Further clinical development of OH2 as single agent or virulence gene was deleted to attenuate the Zhang B, et al. J Immunother Cancer 2021;9:e002224. doi:10.1136/jitc-2020-002224 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-002224 on 9 April 2021. Downloaded from toxicity and enhance tumor selectivity. The ICP47 gene one dose level, the previous lower dose would be defined was removed to help present tumor associated antigens as the maximum- tolerated dose (MTD). The recom- and promote the oncolytic activity. The gene encoding mended dose level of single agent OH2 was determined the human granulocyte- macrophage colony- stimulating on completion of dose-escalation, taking into consider- factor (GM- CSF) was added to potentiate antitumor ation the MTD, safety, biodistribution parameters and immunity.6 Preclinical studies demonstrated that OH2 tumor response. In the phase II dose-expansion part of was genetically and biologically stable,7 and exhibited the study, patients were assigned either to receive single potent oncolytic activity and safety in animal models.6 8 agent OH2 at the recommended dose level, or HX008 Moreover, a specific antitumor immune response and a plus OH2 at dosages proved to be tolerable in phase I of long- term effect to inhibit tumor recurrence and metas- the combination therapy. tasis were observed in a murine colon cancer model The intratumoral injection was performed either treated with OH2.9 These data validated subsequent clin- directly for cutaneous or subcutaneous lesions, or with ical investigation of the drug. ultrasound guidance for deep-located nodes or organ There have been limited reports concerning the appli- metastases. The volume injected to each lesion was based cation of HSV- based oncolytic viruses in solid tumors on the longest diameter of the tumor (≤1.5 cm, up to other than glioma and melanoma. We therefore initiated 1 mL; >1.5 to ≤2.5 cm, up to 2 mL; >2.5 to ≤5.0 cm, up to a phase I/II study in patients with advanced solid tumors 4 mL; >5.0 cm, up to 8 mL). Injection of multiple tumors to evaluate the safety, biodistribution and antitumor was allowed. There were no limits on the number of activity of OH2 as single agent or in combination with lesions that can be injected per patient, but the maximum other anticancer drugs. Meanwhile, with tumor samples volume that can be injected during each visit was 8 mL. obtained from baseline and on- therapy biopsies, we also aim to explore the alterations of the tumor microenviron- Safety and response evaluation ment after OH2 virotherapy. Here we report the results of Adverse events (AEs) and DLTs were graded according treatment with single agent OH2, and OH2 in combina- to the National Cancer Institute Common Terminology tion with HX008, an anti- programmed cell death protein Criteria for Adverse Events (version 5.0). DLT was defined 1 (PD-1) antibody. as any of the following events within the first 3 weeks of therapy that was deemed treatment-related by the investi- gator(s): grade 4 neutropenia lasting over 5 days or febrile METHODS neutropenia; grade 3 thrombocytopenia with bleeding; Patients any other grade 4–5 hematological AEs; grade 3 rash In this open-label, multicenter, phase I/II trial, we over 3 days; grade 3 nausea, vomiting and diarrhea lasting enrolled patients aged between 18 and 75 years with a over 3 days despite appropriate supportive care; grade 3 histologically confirmed advanced solid tumor whose alanine aminotransferase or aspartate aminotransferase disease had progressed despite standard systemic thera- level increase lasting over 7 days; grade 2 proteinuria http://jitc.bmj.com/ pies. Inclusion criteria included having tumor(s) deemed lasting over 7 days; any other grade 3–5 non-hematological safe to inject the virus; at least one measurable lesion AEs. AEs were collected throughout the study treatment as defined in the Response Evaluation Criteria in Solid and for 60 days after the last dose of OH2. Tumors (RECIST), version 1.1; an Eastern Cooperative Tumor assessments were conducted at screening, every Oncology Group performance status score of 0 or 1; and 6 weeks during the first 6 months after treatment initia- adequate organ functions assessed by the complete blood tion, every 8 weeks after 6 months and every 12 weeks after on September 30, 2021 by guest. Protected copyright. count, blood chemistry and coagulation tests. Patients 12 months. Radiographic assessments were performed were excluded if they had symptomatic central nervous using CT or MRI. Measurement of cutaneous or subcu- system metastases, presentations of active infection or an taneous lesions were conducted with calipers.
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