OH2 Demonstrates Tolerability and Combination Activity in Advanced Sarcoma

The oncolytic virus OH2 was tolerable and displayed antitumor activity in combination with the PD-1 inhibitor HX008 in patients with locally advanced or metastatic sarcoma, according to results from a phase 1/2 study published in the Journal for ImmunoTherapy of Cancer.1

The overall response rate (ORR) among evaluable patients who received OH2 monotherapy (n = 7) and those who received OH2 plus HX008 (n = 18) was 0% and 16.7%, respectively; 2 complete responses were reported in the combination cohort. At a median follow-up of 11.9 months, the median progression-free survival (PFS) was 1.41 months (95% CI, 1.15-2.73) and 1.45 months (95% CI, 1.38-5.36), respectively. The median overall survival (OS) was 4.50 months (95% CI, 1.91-8.21) and 18.04 months (95% CI, 8.90-not available), respectively.

In terms of safety, no dose-limiting toxicities were reported and the maximum-tolerated dose of OH2 was not reached during dose escalation. No serious treatment-related adverse effects (TRAEs) or deaths attributed to study treatment were observed.

“Our findings inform the design of future clinical trials investigating oncolytic virus therapies in combination with immune checkpoint inhibitors for sarcoma,” the study authors wrote. “This is particularly relevant for neoadjuvant settings in specific sarcoma subtypes such as angiosarcoma and fibrosarcoma.”

OH2 is a genetically engineered oncolytic virus derived from the wild-type herpes simplex virus (HSV)–2 strain HG52. The virus is constructed with the human granulocyte-macrophage colony-stimulating factor encoding gene and the deletion of the ICP34.5 neurovirulence gene.

Phase 1/2 Study Design

The open-label, non-randomized, multicenter trial enrolled patients with locally advanced or metastatic soft tissue sarcoma who experienced disease progression within 6 months before enrollment. Eligible patients needed to be at least 18 years of age, have 1 or more injectable lesions with a maximum diameter of 5 mm, have received at least 1 line of standard systemic therapy, an ECOG performance status of 0 or 1, and adequate hematological, renal, metabolic, and hepatic function.

Patients received single-agent OH2 or OH2 in combination with HX008. Intratumoral OH2 was administered at a dose of 106, 107, or 108 CCID50/mL every 2 weeks. In the combination group patients also received intravenous HX008 at a fixed dose of 200 mg every 3 weeks; OH2 and HX008 were administered on day 1 of the first cycle then in accordance with their own dosing schedules.

OH2 intratumoral injections were performed directly for cutaneous or subcutaneous lesions and with ultrasound guidance for deep-located nodes or organ metastases. The volume of OH2 injections was based on the longest diameter of the tumor. Injection of multiple tumors was permitted and there were no limits on the number of lesions that could be injected per patient. The maximum volume of OH2 that could be injected during each visit was 8 mL.

The primary end points were safety and tolerability in the phase 1 portion of the study as well as ORR per RECIST 1.1 criteria in phase 2. Secondary end points included duration of response (DOR), PFS, and OS.

At baseline, the median age in the monotherapy (n = 7) and combination cohorts (n = 19) was 45 years (range, 25-65) and 54 years (range, 24-69), respectively. Most patients in both arms had negative HSV-2 serostatus at baseline (100% vs 84.2%) and had distant metastases (71.4% vs 52.6%). Prior immunotherapies consisted of toripalimab-tpzi (Loqtorzi; 14.3% vs 10.5%), sintilimab (Tyvyt; 14.3% vs 15.8%), and tislelizumab-jsgr (Tevimbra; 0% vs 5.3%). Sarcoma histological subtypes included leiomyosarcoma (0% vs 26.3%), angiosarcoma (0% vs 15.8%), bone sarcoma (28.6% vs 10.5%), rhabdomyosarcoma (14.3% vs 0%), fibrosarcoma (0% vs 5.3%), alveolar soft part sarcoma (0% vs 10.5%), liposarcoma (0% vs 5.3%), synovial sarcoma (28.6% vs 5.3%), undifferentiated or unclassified sarcoma (14.3% vs 5.3%), and other subtypes (14.3% vs 15.8%). Patients in both cohorts had a median of 2 (range, 1-5) lesions injected with OH2.

Additional Safety and Efficacy Data

Additional efficacy findings showed that patients who experienced a response to OH2 plus HX008 were comprised of patients with fibrosarcoma (n = 1), liposarcoma (n = 1), and angiosarcoma (n = 2). The patient with liposarcoma had tumor shrinkage of injected lesions but was forced to discontinue therapy due to significant growth of non-injected lesions. The remaining 3 patients experienced durations of response of 3.9 months, 5.5 months, and 6.5 months, respectively. The study authors noted that 1 of the patients with angiosarcoma who experienced a response had previously experienced disease progression following treatment with paclitaxel plus an immune checkpoint inhibitor, implying a synergetic effect of OH2 plus HX008; this patient remained on treatment at the data cutoff.

Most patients in the monotherapy arm experienced an any-grade TRAE (85.7%). Common any-grade TRAEs included fever (57.1%), anemia (28.6%), and decreased white blood cell count (28.6%). Two patients experienced grade 3 or higher anemia.

In the combination cohort, patients experienced any-grade TRAEs at a rate of 84.2%. Common any-grade TRAEs included fever (26.3%), elevated γ-GGT levels (26.3%), and weight loss (21.1%). Grade 3 or higher TRAEs consisted of hypertriglyceridemia (5.3%), nausea (5.3%), anorexia (5.3%), and neck pain (5.3%).

“Intratumoral injection of oncolytic virus OH2 was safe in patients with sarcoma,” the study authors wrote in their conclusion. “Encouraging antitumor activities were observed in patients with angiosarcoma and fibrosarcoma for the OH2/HX008 combination. The effectiveness and low toxicity favor further investigation of OH2 and HX008 in [a] neoadjuvant regimen in selective soft tissue sarcoma subtypes.”

Reference

Tan Z, Wu Y, Fan Z, et al. Intratumoral oncolytic virus OH2 injection in patients with locally advanced or metastatic sarcoma: a phase 1/2 trial. J Immunother Cancer. 2025;13(1):e010543. doi:10.1136/jitc-2024-010543