First oncolytic virus approved for melanoma immunotherapy

ABSTRACT

On 2015, October 27th, the US Food and Drug Administration (FDA) has officially approved talimogene laherparepvec (T-VEC, also known as OncoVEX^GM-CSF) for use in melanoma patients with injectable but non-resectable lesions in the skin and lymph nodes. T-VEC (which is commercialized by Amgen, Inc. under the name of Imlygic®) becomes therefore the first oncolytic virus approved for cancer therapy in the US.

KEYWORDS:

• Granulocyte macrophage colony-stimulating factor
• Imlygic®
• OncoVEX^GM-CSF
• OPTiM
• talimogene laherparepvec
• T-vec

The term “oncolytic virus” refers to a non-pathogenic viral strain that kills malignant cells while virtually sparing their non-transformed counterparts.^1,2 A limited amount of viruses are naturally oncolytic as they display an elevated oncotropism (i.e., they selectively infect neoplastic cells) and mediate a robust cytopathic effect.^1,2 However, several obstacles prevent the use of most naturally occurring viruses for oncolytic virotherapy, including an excessive pathogenic potential, a sub-optimal oncotropism, an elevated susceptibility to neutralization by innate or adaptive immune effectors, and a limited capacity to trigger tumor-targeting immune responses.^3,4 Genetic engineering has been intensively employed throughout the past decade to circumvent these issues and generate oncolytic viral strains with superior clinical activity.^1,2

T-VEC is one of these genetically engineered strains. T-VEC derives from a primary isolate of human herpes simplex virus 1 (HSV-1) known as JS1 (ECACC Accession Number 01010209) that per se demonstrated enhanced oncolytic activity as compared to other clinical HSV-1 isolates and laboratory strains.^5,6 T-VEC was obtained in several consecutive rounds of genetic engineering. First, JS1 was attenuated by functionally deleting both copies of RL1 (encoding the neurovirulence factor ICP34.5), as well as US12 (encoding the neurovirulence factor ICP47).^5,6 Of note, the deletion of US12 converted the late gene US11 into an immediate-early gene driven by the US12 promoter.^5,6 Altogether, these genetic modifications provide T-VEC with the capacity to establish a productive infection in malignant cells (but not in normal cells), most likely because rapidly-dividing cells express a protein that, together with US11 expressed early after infection, can functionally substitute for ICP34.5.^7,8 Finally, one cassette encoding human granulocyte macrophage colony-stimulating factor (GM-CSF) under the control of the cytomegalovirus immediate-early promoter was inserted into each of the non-functional RL1 loci.^5,6 The expression of GM-CSF in the context of viral oncolysis favors the recruitment and activation of antigen-presenting cells,^9,10 hence endowing T-VEC with the ability to promote the initiation of a tumor-targeting immune response.^11-13 Importantly, T-VEC remains susceptible to anti-HSV-1 therapeutics such as acyclovir,^14,15 offering an additional safety control over viral replication and spread.

Results from early Phase I and II trials testing intratumoral T-VEC in patients with various tumors (including melanoma) were very encouraging,^16-18 prompting Amgen, Inc. initiate various Phase III clinical studies, including OPTiM (OncoVEX^GM-CSF Pivotal Trial in Melanoma, NCT00769704).¹⁹ In this context, 436 subjects with Stage IIIb-IV melanoma bearing injectable but not surgically resectable tumors were randomly assigned (at a 2:1 ratio) to receive intralesional T-VEC or subcutaneous GM-CSF. The primary end point of the study was durable response rate (DRR, defined as the rate of objective responses lasting continuously for at least 6 mo), per independent assessment. Secondary end points included overall response rate (ORR) and overall survival (OS).²⁰

As early as on 2013, March 19th, Amgen Inc. released preliminary data from the OPTiM study, indicating that patients in the T-VEC arm exhibited a significantly higher DDR than subjects receiving GM-CSF only.²¹ This announcement generated considerable enthusiasm, and earlier this year (on 2015, April 29th), the US FDA emitted the first formal recommendation supporting the approval of T-VEC for the treatment of melanoma.^22-24 However, it was not until October 27th that the US FDA officially licensed T-VEC for use in melanoma patients with injectable but non-resectable lesions in the skin and lymph nodes (source http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469571.htm).

This decision ensued the release of final data from the OPTiM trial, which confirmed the superiority of intralesional T-VEC over subcutaneous GM-CSF in terms of DRR (16.3% vs. 2.1%), ORR (26.4% vs. 5.7%) and median OS (23.3 mo vs. 18.9 mo).²⁰ Moreover, the administration of T-VEC was associated with a very favorable safety profile, the most common adverse events being fatigue, chills, and pyrexia. The only severe (Grade 3–4) toxicity occurring in more than 2% of patients receiving T-VEC was cellulitis, and no fatal treatment-related adverse events occurred.²⁰

Although H101 (a recombinant oncolytic adenovirus commercialized under the name of Oncorine^®) is licensed by the China Food and Drug Administration (CFDA) for use together with chemotherapy in subjects with refractory head and neck carcinoma since November 2005,²⁵ the addition of oncolytic virotherapy to the clinical armamentarium represents a first-in-history in the US. Based on recent official recommendations emitted by the European Medicine Agency (EMA), T-VEC may soon enter the clinical practice in Europe, too (http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/10/news_detail_002421.jsp&mid=WC0b01ac058004d5c1). Now, it will be interesting to see if t T-VEC can be successfully employed for the treatment of other solid tumors, and to test whether the efficacy of T-VEC can be boosted by combining it with chemotherapy,^26,27 radiation therapy,^28,29 or alternative immunotherapeutic interventions,³⁰ like checkpoint blockers.^31,32 Finally, it will be important to elucidate the molecular and cellular circuitries explaining why T-VEC has been so successful as compared to several other GM-CSF-encoding oncolytic viruses, most of which are still in preclinical or early clinical development.^3,4 Perhaps, T-VEC is able to promote a particularly immunogenic form of cellular demise^33-36 associated with Type I interferon signaling, which is also required for the full-blown efficacy of various chemotherapeutics.^37,38 Further investigation is required to formally address this intriguing possibility.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

Authors are supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; AXA Chair for Longevity Research; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).