Immune responses following intrapleural administration of oncolytic SEPREHVIR in patients with malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) remains a major challenge, with limited therapeutic options. Multifocal intrapleural disease can cause disabling symptoms of pain and breathlessness, in the absence of distant metastases, so an intrapleural treatment approach is attractive. SEPREHVIR (HSV1716) is a mutant oncolytic herpes simplex virus type 1 deleted in the RL1 gene which encodes the protein ICP34.5, a specific determinant of virulence. Mutants lacking the RL1 gene are capable of specific replication in cancer cells and inducing anti-tumour immune responses. Clinical studies with SEPREHVIR have been completed in adult glioma, melanoma, squamous cell head and neck cancer, and studies are ongoing in both pediatric CNS and non-CNS solid tumors and MPM. In total, 92 patients have received SEPREHVIR and the virus is well-tolerated with no spread to surrounding normal tissue or no shedding in patients. SEPREHVIR selectivity for replication only in tumour cells and intimations of efficacy and immuno-stimulatory potential have been demonstrated.We are currently conducting a phase I/IIa trial to determine the safety and potential for efficacy of SEPREHVIR given intrapleurally to patients with MPM. Patients receive 1x107iu SEPREHVIR through their pleural catheter on one, two or four occasions a week apart, in three separate patient cohorts. To date 9 patients have been treated, 3 in each cohort and SEPREHVIR has been well-tolerated with few adverse events in any patients. Pleural fluid and plasma samples have been collected pre- and post treatment and analysed to assess patient responses to SEPREHVIR administration.HSV DNA was detected in the pleural fluids of most patients and in some persisted for at least two weeks post-administration. Analysis of pleural fluid cytokines/chemokines by ELISA indicated that they were rich in IL-6, MIG and VEGF. Post SEPREHVIR administration there were increased levels of IFNγ, IP-10, MIG, TNFα and IL-6 in most patients. There were variable responses of VEGF, IL-2, IL-10 and IL-12 after SEPREHVIR administration with IL-2, IL-10 and IL-12 increases most notable in patients receiving 4 doses of SEPREHVIR. IL-1α, IL-4, IL-21, and IFNα were not detected pre-treatment and showed little or no response to SEPREHVIR administration.Analysis of plasma samples indicated strong anti-HSV IgG responses post SEPREHVIR administration, particularly after 2 and 4 doses. Interestingly, in most patients, these were accompanied by the appearance of a novel anti-tumour IgG response as detected by immunoblotting against extracts from MPM cell lines. Thus, oncolytic SEPREHVIR has immunotherapeutic potential capable of inducing novel anti-tumour immune responses in patients.Citation Format: Kirsty Learmonth, Lynne Braidwood, Penella Woll, Joe Conner. Cytokine responses following intrapleural administration of oncolytic HSV SEPREHVIR® in patients with malignant pleural mesothelioma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B033.