Biodistribution, shedding, and transmissibility of the oncolytic virus talimogene laherparepvec in patients with melanoma

Abstract

Background: Talimogene laherparepvec (T-VEC) is an intralesionally delivered, modified herpes simplex virus type-1 oncolytic immunotherapy. The biodistribution, shedding, and potential transmission of T-VEC was systematically evaluated during and after completion of therapy in adults with advanced melanoma.

Methods: In this phase 2, single-arm, open-label study, T-VEC was administered into injectable lesions initially at 10⁶ plaque-forming units (PFU)/mL, 10⁸ PFU/mL 21 days later, and 10⁸ PFU/mL every 14 (±3) days thereafter. Injected lesions were covered with occlusive dressings for ≥1 week. Blood, urine, and swabs from exterior of occlusive dressings, surface of injected lesions, oral mucosa, anogenital area, and suspected herpetic lesions were collected throughout the study. Detectable T-VEC DNA was determined for each sample type; infectivity was determined for all swabs with detectable T-VEC DNA.

Findings: Sixty patients received ≥1 dose of T-VEC. During cycles 1-4, T-VEC DNA was detected in blood (98·3% of patients, 36·7% of samples), urine (31·7% of patients, 3·0% of samples) and swabs from injected lesions (100% of patients, 57·6% of samples), exterior of dressings (80% of patients,19·5% of samples), oral mucosa (8·3% of patients, 2·5% of samples), and anogenital area (8·0% of patients, 1·1% of samples). During the safety follow-up period, T-VEC DNA was only detected on swabs from injected lesions (14% of patients, 5.8% of samples). T-VEC DNA was detected in 4/37 swabs (3/19 patients) of suspected herpetic lesions. Among all samples, only those from the surface of injected lesions tested positive for infectivity (8/740 [1·1%]). Three close contacts reported signs and symptoms of suspected herpetic origin; however, no lesions had detectable T-VEC DNA.

Interpretation: Using current guidelines, T-VEC can be administered safely to patients with advanced melanoma and is unlikely to be transmitted to close contacts with appropriate use of occlusive dressings. FUND: This study was funded by Amgen Inc.: ClinicalTrials.gov, NCT02014441.

Keywords: Biodistribution; Melanoma; Oncolytic immunotherapy; Shedding; T-VEC; Talimogene laherparepvec; Transmission.

Fig. 1

Sampling schedule. ^aSwab taken in clinic within 3 days of the occurrence of reportable lesion. ^bAny potential or known unintended exposure to T-VEC was reported within 24 h of the investigator's knowledge of the event of exposure. Swabs were taken with the consent of the individual. Abbreviations: T-VEC, talimogene laherparepvec.

Fig. 2

Patient incidence of detectable T-VEC DNA in (A) blood, (B) urine, (C) surface of injected lesions, (D) exterior of occlusive dressings, (E) oral mucosa, and (F) anogenital area. HSV-1 serostatus at baseline was missing for 3 patients. Samples were taken on day 30 and/or 60 of the safety follow-up period; no swabs from occlusive dressings were taken during the safety follow-up period. N = number of patients with samples collected; n = number of patients positive for T-VEC DNA. Abbreviations: HSV-1, herpes simplex virus type 1; T-VEC, talimogene laherparepvec.

Fig. 3

Sample incidence of detectable T-VEC DNA in (A) blood, (B) urine, (C) surface of injected lesions, (D) exterior of occlusive dressings, (E) oral mucosa, and (F) anogenital area. HSV-1 serostatus at baseline was missing for 3 patients. Samples were taken on days 30–60 of the safety follow-up period; no swabs from occlusive dressings were taken during the safety follow-up period. A number of samples taken throughout the study contained detectable T-VEC DNA below the lower limit of quantification: 79/383 (21%) samples from blood, 17/31 (55%) samples from urine, 77/741 (10%) swabs from the surface of injected lesions, 52/212 (25%) swabs from the exterior of occlusive dressings, 3/12 (25%) swabs from the oral mucosa, and 5/7 (71%) swabs from the anogenital area. N = number of samples collected; n = number of samples positive for T-VEC DNA. Abbreviations: HSV-1, herpes simplex virus type 1; T-VEC, talimogene laherparepvec.

Fig. 4

Quantification of T-VEC DNA by qPCR in patient samples. (A) blood, (B) urine, (C) surface of injected lesions, (D) exterior of occlusive dressings, (E) oral mucosa, and (F) anogenital area. Samples were collected throughout the treatment period and at the 30- and 60-day safety follow-up visits. N = number of patients tested; n = number of patients with T-VEC DNA equal to or above the lower limit of quantification. Upper and lower edges of the box represent Q3 and Q1, respectively. Median is presented as a horizontal bar in the box, and mean is presented as a diamond. Upper and lower whiskers represent the maximum and minimum, excluding outliers. Abbreviations: D, day; Pre, predose; qPCR, quantitative polymerase chain reaction; T-VEC, talimogene laherparepvec.