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 10⁵ to 10⁷ 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 +4 consistent with de novo virus replication. Two patients had transient focal increases in metabolic activity on ¹⁸fluorine-deoxyglucose 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; 23(14); 3566-74. ©2017 AACR.

Figure 1

Inflammatory reactions following virus injection as detected by PET/CT. Baseline images, needle tracks and injection sites (arrows), and follow up scans are shown for two patients who experienced a transient increase in SUV uptake following virus injection that ultimately returned near baseline. Although initially interpreted as tumor progression, in retrospect the spontaneous decrease suggests the uptake was due to a transient inflammatory reaction to virus (pseudoprogression). (A) Patient HSV06. The tumor mass is outlined in white, C= Cycle, D=Day. Notice the area of uptake drops to zero, suggesting tumor necrosis in the exact geographic distribution of the uptake. (B) Patient HSV08. Notice the pleural effusion (white arrows) that developed coincident with the increased PET signal, both of which spontaneously resolved. In addition to the injected right chest wall lesion, the uninjected left hilar lesion also showed a transient increase in PET signal suggesting a systemic effect.