Intratumoral Injection of HSV1716, an Oncolytic Herpes Virus, Is Safe and Shows Evidence of Immune Response and Viral Replication in Young Cancer Patients

Abstract

Purpose: HSV1716 is an oncolytic herpes simplex virus-1 (HSV-1) studied in adults via injection into the brain and superficial tumors. To determine the safety of administering HSV1716 to pediatric patients with cancer, we conducted a phase I trial of image-guided injection in young patients with relapsed or refractory extracranial cancers.Experimental Design: We delivered a single dose of 10 5 to 10 7 infectious units of HSV1716 via computed tomography-guided intratumoral injection and measured tumor responses by imaging. Patients were eligible for up to three more doses if they achieved stable disease. We monitored HSV-1 serum titers and shedding by PCR and culture.Results: We administered a single dose of HSV1716 to eight patients and two doses to one patient. We did not observe any dose-limiting toxicities. Adverse events attributed to virus included low-grade fever, chills, and mild cytopenias. Six of eight HSV-1 seronegative patients at baseline showed seroconversion on day 28. Six of nine patients had detectable HSV-1 genomes by PCR in peripheral blood appearing on day þ4 consistent with de novo virus replication. Two patients had transient focal increases in metabolic activity on 18 fluorinedeoxyglucose PET, consistent with inflammatory reactions. In one case, the same geographic region that flared later appeared necrotic on imaging. No patient had an objective response to HSV1716.Conclusions: Intratumoral HSV1716 is safe and well-tolerated without shedding in children and young adults with late-stage, aggressive cancer. Viremia consistent with virus replication and transient inflammatory reactions hold promise for future HSV1716 studies. Clin Cancer Res; 1-9. Ó2017 AACR.

PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy

“…In our study, imaging of animals treated intratumorally with NDV and with adoptively transferred luciferase-expressing T cells revealed increased T cell infiltration 4-5 days after NDV treatment ( Figure 5). In a trial conducted by Streby et al, intratumoral administration of HSV1716, an oncolytic herpes virus, showed transient increases in fluorodeoxyglucose-PET (FDG-PET) activity in some patients, consistent with a tumor inflammatory reaction (51). This creates a strong rationale for in vivo monitoring of tumor infiltration, perhaps specifically by imaging CD8 + lymphocytes.…”

TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma

“…The loss of this factor, which normally counteracts the interferon and protein kinase R (PKR)-mediated shutdown of virus gene translation, restricts HSV1716 replication to cells in which these pathways are disabled (i.e., tumor cells) 23 . HSV1716 exhibits lytic activity against a wide variety of cancers and has been safely administered in multiple clinical trials, including an on-site trial for pediatric patients 24, 25. HSV1716 has also been shown to induce multiple immunostimulatory activities, such as the production of pro-inflammatory chemokines, enhanced dendritic cell phagocytosis and antigen presentation, and increased T cell recruitment to the site of the tumor 6, 26, 27.…”

Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis

“…A limitation of our study is that the oncolytic HSV1 platforms that have progressed to clinical trials are attenuated through gamma34.5 (g34.5) gene deletion. Using the clinically relevant g34.5-deleted HSV1-1716 [34], we have observed a similar augmentation of viral infection by asTORi treatment in the transformed NT2196 cell line. Nonetheless, additional experiments with g34.5-deleted HSV1 are necessary to fully address the clinical implications of the findings presented here.…”

“…We found that the increased GFP expression in the transformed NT2196 cells relative to DMSO-treated cells begins only at 24 hours post-infection, and that asTORi strongly suppressed the virus in the normal NMuMG cells ( S1E Fig ). Importantly, this effect was not unique to HSV1-dICP0, as g34.5-deleted HSV1-1716, that has undergone clinical development [34], also led to an increase in fluorescence upon treatment with PP242 as compared to DMSO control in the transformed NT2196 cell line ( S1E Fig ). However, the increase with g34.5-deleted HSV1-1716 was not as dramatic as seen with HSV1-dICP0.…”