Oncolytic Virotherapy for Melanoma Brain Metastases, a Potential New Treatment Paradigm?

Abstract

Introduction: Melanoma brain metastases remain a devastating disease process with poor prognosis. Recently, there has been a surge in studies demonstrating the efficacy of oncolytic virotherapy for brain tumor treatment. Given their specificity and amenability to genetic modification, the authors explore the possible role of oncolytic virotherapy as a potential treatment option for patients with melanoma brain metastases. Methods: A comprehensive literature review including both preclinical and clinical evidence of oncolytic virotherapy for the treatment of melanoma brain metastasis was performed. Results: Oncolytic virotherapy, specifically T-VEC (Imlygic™), was approved for the treatment of melanoma in 2015. Recent clinical trials demonstrate promising anti-tumor changes in patients who have received T-VEC; however, there is little evidence for its use in metastatic brain disease based on the existing literature. To date, only two single cases utilizing virotherapy in patients with metastatic brain melanoma have been reported, specifically in patients with treatment refractory disease. Currently, there is not sufficient data to support the use of T-VEC or other viruses for intracranial metastatic melanoma. In developing a virotherapy treatment paradigm for melanoma brain metastases, several factors must be considered, including route of administration, need to bypass the blood–brain barrier, viral tumor infectivity, and risk of adverse events. Conclusions: Evidence for oncolytic virotherapy treatment of melanoma is limited primarily to T-VEC, with a noticeable paucity of data in the literature with respect to brain tumor metastasis. Given the promising findings of virotherapy for other brain tumor types, oncolytic virotherapy has great potential to offer benefits to patients afflicted with melanoma brain metastases and warrants further investigation.

Epidemiology, management, and treatment outcomes of metastatic spinal melanoma

“…Among these are ICIs targeting programmed death receptor-1 (PD-1) and its ligand (e.g., nivolumab, pembrolizumab) or cytotoxic T-lymphocyte antigen-4 (e.g., ipilimumab), as well as targeted therapies against melanoma with the BRAF V600E mutation that confers increased risk of CNS metastasis (e.g., vemurafenib, dabrafenib). 2 , 39 Immunotherapy portends improved progression-free survival in patients with melanoma metastatic to the CNS, 8 , 9 but prognosis remains poor, and the optimal management of patients with metastatic spinal melanoma likely entails individualized treatment combining surgery, radiotherapy, and immunotherapy. 39 , 46 …”

“…High-quality prospective data on treatment outcomes for immunotherapy in metastatic spinal melanoma are needed, although this need is complicated by its generally low incidence and the fact that patients with melanoma metastatic to the CNS are often excluded from clinical trials (e.g., concerns of poor overall survival, emergent need to initiate radiation for patients with symptomatic spinal metastasis). 2 , 55 …”

“…Oncolytic virotherapy, which involves intratumoral delivery of genetically engineered oncolytic virus (e.g., talimogene laherparepvec [T-VEC], a modified herpes simplex virus), has shown promise in treating melanoma metastatic to the CNS via an abscopal effect. 2 While T-VEC is the most well-studied of these treatments, other oncolytic viral vectors are currently being investigated for their potential in treating metastatic CNS melanoma. 61 Other approaches include tumor-infiltrating lymphocyte therapy, which utilizes expansion of a patient's autologous T-cells, manipulation ex vivo , and re-infusion into the patient to generate an anti-tumor response.…”

“…Melanoma metastases to the central nervous system (CNS) occur in 10–40% of melanoma patients depending on stage at diagnosis, rising up to 80% in autopsy series. 1 , 2 In contrast to intracranial metastases, metastatic spinal melanoma is particularly rare, representing a late event in the evolution of the disease, with estimates for median overall survival of 4 months, 2-year survival of 0.2%, and 5-year survival of 0%. 3 , 4 , 5 Surgery and radiotherapy are mainstays of treatment.…”

Oncolytic virotherapy using neural stem cells as a novel treatment option for glioblastoma multiforme

“…H‐1PV can kill glioma cells that are resistant to cisplatin and TRAIL by increasing the aggregation of cathepsins B and L and reducing the quantities of cystatins B and C, which act as inhibitors of these proteolytic enzymes (TNF‐related apoptosis‐inducing ligand). As a result, glioma cells that have become resistant to cisplatin and TRAIL are destroyed 87,88 . The method has supposedly been successful.…”