Talimogene laherparepvec: First in class oncolytic virotherapy

Abstract

Oncolytic viruses represent a novel drug class in which native or modified viruses mediate tumor regression through selective replication within and lysis of tumor cells as well as induction of systemic antitumor immunity capable of eradicating tumor at distant, uninjected sites. Talimogene laherparepvec (TVEC) is a type I herpes simplex virus genetically modified to preferentially replicate in tumor cells, enhance antigen loading of MHC class I molecules and express granulocyte-macrophage colony-stimulating factor to increase tumor-antigen presentation by dendritic cells. It is presently the only oncolytic virus approved by the FDA with an indication for advanced melanoma based upon improved durable response rate in a randomized, phase III trial. Clinical trials are underway in melanoma investigating TVEC as neoadjuvant monotherapy and in combination with checkpoint inhibitors for unresectable disease as well as in an array of other malignancies. It is appropriate to review TVEC's biology mechanism of action, clinical indication and future directions as a prototype of the burgeoning class of oncolytic viruses.

Immunotherapy for pediatric brain tumors

“…At least 50 clinical trials are ongoing using oncolytic viruses to treat cancer patients, mostly adults with non-CNS solid tumors. The oncolytic virus talimogene laherparepvec (TVEC), a modified type I herpes simplex virus for adults with advanced melanoma, is the first oncolytic virus to receive FDA approval [24] . Mechanistically, oncolytic viruses predominantly function through a combination of tumor cell lysis and stimulation of the innate immune system through DAMP and pathogen-associated molecular patterns (PAMP) [25] .…”

“…However, oncolytic viruses are now regarded as immunotherapy for which efficacy depends on activating an endogenous anti-tumor immune response [26] . [24] . The virus induces tumor cell death and causes DAMP and PAMP expression within the tumor.…”

“…The virus induces tumor cell death and causes DAMP and PAMP expression within the tumor. Additionally, the viral genome is genetically modified to increase MHC class I expression and to secrete GM-CSF, which promotes dendritic cell accumulation and antigen presentation to prime an adaptive immune response [24] . Taken together, this first-in-class agent represents how oncolytic viruses can be modified to stimulate innate immunity and readily combined with conventional and immunebased therapies.…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…Oncorine (H101), a genetically modified oncolytic adenovirus (OAd), was approved by the State Food and Drug Administration (SFDA, now the National Medical Products Administration (NMPA)) in 2005 for the treatment of nasopharyngeal carcinoma in China [39,40]. Talimogene laherparepvec (T-VEC; brand name Imlygic) was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of advanced melanoma in 2015 [41,42].…”

Rash after a single injection of T‐VEC

“…A false-negative PCR result was ruled out using a gel control. Given that UL30 DNA polymerase is not affected by the above-mentioned genetic modifi cations, T-VEC can be detected with standard HSV1 PCR probes [ 2 ] .…”