Intratumoral OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: a multicenter, phase I/II clinical trial

Abstract

BackgroundOH2 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.MethodsIn 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 (106, 107 and 108CCID50/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.ResultsBetween 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 108CCID50/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.ConclusionsIntratumoral 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.

Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade

“…Zhang et al showed that oHSV therapy led to an increase in tumour-infiltrating CD4 and CD8 T cells and a decrease in Treg and suppressive TAM in a mouse model of pancreatic ductal adenocarcinoma (PDAC). PDAC is a notoriously immune-excluded, "cold" tumour, with a TME comprising immunosuppressive Treg, tumour associated macrophages (TAM), immunosuppressive cytokines and physical barriers to T cell infiltration such as CAFs and a desmoplastic stroma (52). Transcriptome profiling of immune cells following treatment showed enrichment of PD-1, LAG-3 and TIM-3 in the CD8 T cell population, and OX40 and CTLA-4 in the CD4 population (53).…”

In Situ Cancer Vaccination and Immunovirotherapy Using Oncolytic HSV

“…T-VEC is currently in clinical trials for pancreatic cancer, non-melanoma skin cancer, breast cancer, and sarcoma. OH2 , oHSV-2 expressing GM-CSF with a similar structure to that of T-VEC, has entered clinical trials in China for metastatic solid tumors with injectable lesions (NCT04386967) [ 157 ].…”

“…HF10 ( Figure 4 ) was evaluated in a phase II clinical trial in combination with ipilimumab in advanced melanoma with a best overall response (BOR) of 41% [ 72 ]. In a phase I/II clinical trial of OH2 (T-VEC-like oHSV-2) alone or in combination with anti-PD-1 (HX008) in patients with advanced solid tumors with injectable lesions, two of 33 patients taking OH2 alone and two of 12 in the combination-treated group had an immune partial response (iPR) that was durable [ 157 ]. Increases in PD-L1 + cells and CD8 + T cells after OH2 alone were observed in most evaluated patients relative to baseline, irrespective of response [ 157 ].…”

“…In a phase I/II clinical trial of OH2 (T-VEC-like oHSV-2) alone or in combination with anti-PD-1 (HX008) in patients with advanced solid tumors with injectable lesions, two of 33 patients taking OH2 alone and two of 12 in the combination-treated group had an immune partial response (iPR) that was durable [ 157 ]. Increases in PD-L1 + cells and CD8 + T cells after OH2 alone were observed in most evaluated patients relative to baseline, irrespective of response [ 157 ]. Among 40 patients treated with OH2 alone, only two were seropositive for HSV-2 at baseline and 26 seroconverted after treatment [ 157 ].…”

“…Increases in PD-L1 + cells and CD8 + T cells after OH2 alone were observed in most evaluated patients relative to baseline, irrespective of response [ 157 ]. Among 40 patients treated with OH2 alone, only two were seropositive for HSV-2 at baseline and 26 seroconverted after treatment [ 157 ]. In mouse syngeneic rhabdomyosarcoma models, tumors from a rhabdomyosarcoma cell line expressing high MHC I (M3-9-M) responded to HSV1716 and anti-PD-1, whereas tumors with MHC I low (76–9) did not respond [ 62 ].…”