Oncolytic Herpes simplex virus - 1 for the treatment of melanoma

Oncolytic viruses (OVs) are native or modified viruses that selectively replicate in and lyse tumor cells. The ability of OVs to selectively lyse tumor cells is attributed to disruption of both oncogenic cell signaling pathways and anti-viral machinery in cancer cells. In melanoma, rapidly dividing cells contain excessive pools of nucleotides that can also be used to enhance replication of attenuated OVs in these cells (1). In addition to the direct lytic effects, OVs are also thought to initiate innate and adaptive immune responses that contribute to both a direct and bystander effect that can promote tumor regression at injected and uninjected sites. The proof-of-concept for OVs in melanoma has recently been confirmed using Talimogene laherparepvec (Imlygic™; T-VEC), a modified form of herpes simplex virus-1 (HSV-1). T-VEC was generated from the JS1 staring of HSV-1 in which the infected cell protein (ICP) 34.5 neurovirulence genes are deleted to limit neurotoxicity and enhance cancer cell specific replication (2). T-VEC also contains a deletion of the herpes ICP47 gene, which otherwise functions to block peptide transport through the transporter associated with antigen processing (TAP) machinery, which the virus uses to avoid immune detection. In the absence of ICP47, tumor-derived and viral peptides should be presented and result in immune recognition. To further enhance anti-tumor immunity, two copies of the human GM-CSF gene have been encoded in T-VEC to promote dendritic cell infiltration and maturation at the tumor site and enhance subsequent tumor-associated antigen presentation to T cells. Therapeutic responses to T-VEC are often limited and targeted therapies such as BRAF and MEK inhibitors often fail due to recurrence of disease in melanoma. To date, combination MAPK inhibition and oncolytic virus therapy has not been clinically tested but this may be an important regimen to consider given the potential for combining agents acting at different parts of the cancer-immunity cycle. Thus, we hypothesized that MAPK inhibition would improve oncolytic virus responses since viral infection could help activate a more robust immune response. Further, we sought to evaluate this concept in melanoma given the frequency of BRAF mutations and the availability of approved MAPK inhibitors and an oncolytic virus for clinical testing. Here, we report a synergistic in vitro and in vivo therapeutic effect for MEK inhibition administered with T-VEC in both human xenograft and immune competent melanoma models. Oncolytic activity was not dependent on BRAF mutation status but was associated with increased viral replication, and the presence of melanoma antigen specific CD8+ T cells and basic leucine zipper transcription factor ATF-like 3 (Batf3+) CD103+ / CD8+ dendritic cells. In addition, we observed that combination treatment resulted in increased PD-1 and PD-L1 expression and found that therapeutic activity could be further expanded when PD-1 blockade was added to the treatment regimen. These data support triple combination therapy with MEK inhibition, oncolytic viruses and PD-1/PD-L1 checkpoint blockade for the treatment of melanoma. A better understanding of how T-VEC can kill melanoma tumor cells might also suggest new targets for combination therapy in melanoma and potentially other tumors permissive to oncolytic virus infection (3). Thus, next we sought to explore the molecular factors involved with T-VEC-mediated lysis melanoma cells and determine which intracellular factors are important for promoting viral replication and promoting anti-tumor immunity. We hypothesized that T-VEC would induce lysis through release of defined Damage-associated molecular patterns (DAMPs) and would promote T cell recruitment to established melanomas through type 1 interferon-related factors, as well as a pro-inflammatory gene signature profile. In addition, we found that specific components of the anti-viral machinery, such as STING, were critical for both T-VEC permissive replication and induction of host anti-tumor immunity. These data support the role of T-VEC in overcoming STING deficiency in melanoma cells and confirms how T-VEC mediates melanoma cell death and triggers innate and adaptive anti-tumor immunity. These data collectively enhance our understanding on how T-VEC can activate anti-tumor immune responses, further help to design rational clinical trials combining oncolytic Herpes simplex viruses and other approved agents in melanoma.Ph.D.Includes bibliographical reference