Infection Control & Hospital Epidemiology
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Table 1. Summary Viral Shedding and Safety Data Reported From Trials Involving Talimogene Laherparepvec (TVEC) as Mono- or Combination Therapy
Trial Agent(s) (Evaluable Subjects)
TVEC (n=60) Tumor Type
Body Sites Evaluated for Shedding
Melanoma Blood Urine
Exterior of dressing
Assay Type Key Findings (Notes) qPCR
Any postprocedure collection positive for TVEC DNA on cycles 1–3 of treatment:
Blood: 98% (all but 1 patient cleared by end of cycle 3) Urine: 31.7% (100% cleared) Outside of occlusive dressing: 80%. Surface of injected lesions: 11.7%
TVEC and ipilimumab26 Melanoma N/A N/A
Adverse events in phase 2 TVEC +ipilimumab vs ipilimumab alone:
Influenza like illness: 26 (27%) vs 1 (1%) Oral herpes: 5 (5%) vs 0 (0%) [TVEC vs wild-type distinction not made] Injection site inflammation: 1 (1%) vs 0 ALT elevation: 7 (7%) vs 4 (4%). AST elevation: 9 (10%) vs 5 (5%) Erythematous rash: 3 (3%) vs 1 (1%) Maculo-papular rash: 6 (6%) vs 2 (2 %)
TVEC (n=17) Pancreatic
TVEC and pembrolizumab SCC (head/ neck)
TVEC vs GM-CSF (292 TVEC, 127 GM-CSF)
Blood Urine
qPCR Presumed herpetic lesions qPCR Melanoma N/A N/A
Detectable TVEC DNA (duration not specified) Blood: 5 (29%) Urine: 7 (41%)
[Pending anticipated completion in 2020]
16 (5.5%) patients in TVEC arm had HSV-related adverse events compared to 2 (1.6%) in the GM-CSF (control) arm.
TVEC related HSV infections included oral herpes (n=15) and herpetic keratitis (n=1)
7 (2.4%) of TVEC arm developed cellulitis > grade 3 OncoVEX – precursor to
TVEC (HSVþGM-CSF)14 (n=17)
TVEC18 (n=50) Multiple
Blood Urine
Dressing, injection site New lesions
Melanoma Injection site swab Urine
qPCR Plaque Assay
Plaque Assay
Virus detected in blood within 8 h (n=9) and up to 1 week (n=1)Low level virus detected at tumor surface up to 2 weeks (n=3)
1 superficial swab was positive after second TVEC injection All urine collected 1–48 h after injection were negative.
Note. ALT, alanine aminotransferase; AST, aspartate transaminase; HSV, herpes simple virus; N/A, not available; qPCR, quantitative polymerase chain reaction; SCC, squamous cell carcinoma.
modified virus is inclusion of a GM-CSF encoding gene to evoke systemic antitumor effects and durable immune response beyond the site of injection.11 Despite these genetic modifications, the viral thymidine kinase
(TK) gene is unchanged, preserving susceptibility to a common antiviral medication, acyclovir.12,13 Viral detection by commer- cially available assays also remains unperturbed due to preserva- tion of target gene regions for these assays in TVEC. For patients with suspected infection after TVEC, commercially avail- able polymerase chain reaction (PCR) testing for cutaneous lesions, cerebrospinal fluid, and blood may be used for viral detec- tion, but the distinction from the wild-type virus requires special- ized testing available only through the drug manufacturer.
Safety profile, viral shedding, and risk of local and disseminated infection in TVEC recipients
The foremost concern with oncolytic viral agents is the risk of uncontrolled replication in vivo and possible transmission to close contacts, other patients, and HCWs. With TVEC, initial concerns centered on the risk of developing disseminated herpes infection, including from reversion to wild-type HSVand manifesting as oral and cutaneous herpes, herpetic keratitis, herpetic whitlow, and dis- seminated herpes.12,14–16
The safety of TVEC is now reported in several primary clinical
trials and expanded access outcomes trials (Table 1). Overall, adverse events related to the administration of TVEC are reported to be minor and local. In phase 1 studies primarily evaluating the local administration of TVEC, the duration and intensity of local inflammatory reactions were more pronounced among HSV sero- negative patients.14 Peak viral recovery from blood (n=17, 85% ) and urine (n=4, 20%) occurred on the day of treatment and was notably absent from injection site vesicular lesions in this single study.17 Phase 2 studies confirmed that HSV antibody negative patients seroconverted after treatment with TVEC.18 No estab- lished cases of disseminated HSV have been reported in any patients included in the pivotal clinical trials, although FDA- mandated postmarketing evaluations are ongoing (Table 1).19,20 Since its approval in 2015, more than 300 cases of adverse
events involving TVEC have been reported and registered in the FDA Adverse Event Reporting System (FAERS) public dash- board.21 Of these 333 cases, 121 are categorized as serious cases, including 21 deaths, but none are specified as disseminated HSV infection. A single FDA warning related to TVEC and noting concern for disseminated HSV infection was issued in 2016, but outcomes from the investigation prompted by this warning have not yet been publicly reported. An FDA-mandated postmarketing study to characterize the long-term risk of herpetic infection in
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