Author(s): Douglas B Johnson [*] aff1 , Igor Puzanov aff1 , Mark C Kelley aff2
GM-CSF; HSV; immune therapy; injectable; melanoma; oncolytic; talimogene laherperepvec; T-VEC
Melanoma is an aggressive cutaneous malignancy that is responsible for [greater than]9000 deaths in the USA annually [1 ]. The prognosis for advanced melanoma has traditionally been quite poor with a median overall survival of 6-9 months [2 ]. Local or regional disease may be cured with surgical treatment in many patients, but relapse is common in patients with high risk disease. Five-year survival rates vary widely by American Joint Committee on Cancer (AJCC) stage, ranging from [greater than]95% for stage IA ([less than]1-mm thickness) to [less than]30% for stage IIIc (spread to 4+ lymph nodes or both nodal and in-transit metastasis) [3 ]. Talimogene Laherperepvec (T-VEC), an engineered oncolytic herpes simplex type 1 virus, is directly injected into melanoma tumors with regional or cutaneous metastatic spread, and is reviewed in detail in this manuscript. First, however, we will discuss factors that influence T-VEC use in the context of other melanoma therapeutics.
Two clinical presentations relatively unique to melanoma directly influence the use of injectable immune therapies such as T-VEC. First, in-transit metastases occur when melanoma cells spread to the dermal lymphatics and present as cutaneous or subcutaneous lesions, generally between a primary tumor and its regional lymphatic basin [4 ]. While this represents only regional disease, lesions can be quite numerous, making surgical resection difficult. Second, melanoma metastases have tropism for the skin, and may metastasize only to subcutaneous or cutaneous sites. In these cases, metastatic spread may range from a single site of disease to multifocal, disseminated skin and soft tissue involvement. In both of these clinical scenarios, all melanoma lesions are directly visible or accessible, but surgical therapy may not be optimal due to the extent of disease and high risk of relapse. Understanding how to treat these patients has been a major research focus and is particularly relevant for T-VEC therapy.
Overview of regional & systemic melanoma therapies
Many patients with in-transit disease have disease confined to a single limb, which is amenable to regional therapy. This may consist of either isolated limb perfusion (ILP) or isolated limb infusion (ILI). Both techniques involve the administration of high-dose chemotherapy (typically, single agent melphalan) to the isolated vascular system of the limb with hyperthermia. The vascular system is isolated by surgical cannulation (ILP), or percutaneous catheterization and tourniquet (ILI). Overall response rates of up to 79% for ILP and 84% for ILI have been reported [5,6 ]. Complete response rates are reported to be as high as 54% for ILP and 38% for ILI, many of which are durable. Unfortunately, many patients fail to respond or have disease outside the perfusion field that is not amenable to therapy. The morbidity of these interventions is also significant, with major complication rates of up to 20% and amputation rates of up to 3% reported in some historical series [5,6 ].
Other therapies have been proposed for...