Oncolytic herpesvirus therapy for mesothelioma: A phase I/IIa trial of intrapleural administration of HSV1716 (NCT01721018)

Abstract

Background: Malignant Pleural Mesothelioma (MPM) remains a major challenge with limited therapeutic options. Disease is frequently confined to the pleura, distant metastases are uncommon and intrapleural treatment is therefore appealing. HSV1716 is a 34.5null oncolytic herpes simplex virus which, in pre-clinical studies, demonstrates cancer cell-specific HSV1716 infection and oncolysis and an anti-tumor immune response. We assessed the safety and potential for efficacy of intrapleural HSV1716 in patients with inoperable MPM. Methods: We performed an open label, dose escalation, phase I/IIa trial of intra-pleural HSV1716. Patients with a histological diagnosis of MPM and indwelling pleural catheter (IPC) were eligible if they had performance status ≤2 and adequate hematologic, renal and liver function. Patients received 1x107pfu HSV1716 through their IPC on 1, 2 or 4 occasions a week apart, in 3 separate cohorts. The primary objective was to determine the safety and tolerability of intra-pleural HSV1716. The secondary objectives were to assess HSV1716 replication and patient immune responses in pleural fluid and blood. An exploratory objective was to assess tumour response by CT, using modified RECIST criteria. Results: Twelve patients were treated, 3 received 1 dose of intrapleural HSV1716, 3 received 2 doses and 6 received 4 doses. HSV1716 was well-tolerated with no HSV1716- related SAE and 17 HSV1716-related transient Grade 1-2 AEs. Evidence of HSV1716 replication (n=9) and pleural Th1 cytokine responses (n=8) were observed. Novel anti-tumor IgG responses were detected post treatment and their antigen targets identified by protein array. CT analysis on day 57 indicated 6 patients with stable and 6 patients with progressive disease. Median survival from treatment was 15mths for all patients and 18mths in patients with evidence of a Th1 immune response (n=8). Conclusions: The study demonstrated an acceptable safety profile of intra-pleural HSV1716 with evidence of viral replication and anti-tumour immunogenicity. This supports further studies inMPM, possibly involving combination with immune checkpoint inhibitors.