**5. Conclusion**

Laherparepvec is a genetically engineered oncolytic virus. It is a genetically modified HSV-1 laherparepvec is used for the treatment of melanoma. It works in two different ways: it replicates more actively in the tumour cells. This causes lysis of the tumour cells. Viral particles and tumour-associated antigens are released from the cells. The viral cells can preferentially target more tumour cells. The tumour antigen can induce an immune response, which is potentiated by the expression of GM-CSF in the laherparepvec. Laherparepvec functions by exploiting the protein kinase R (PKR) pathway. This pathway suppresses viral replication in healthy cells. The usual defence mechanism infected susceptible cell protein 34.5 is usually responsible for overcoming the PKR pathway in HSV. However, laherparepvec is genetically modified to delete the infected susceptible cell protein 34.5 in HSV-1, leaving the cells vulnerable to degradation by PKR. In healthy cells, the PKR pathway is active and causes inactivation of the laherparepvec pathway. However, in the case of tumour cells, PKR is inactive. This leads to the virus actively replicating selectively in the tumour cells. Furthermore, there is a downregulation of type 1 IFN pathway in tumour cells. This leads to a further susceptibility of tumour cells to laherparepvec [54]. The OPTiM trial randomised patients to either intralesional laherparepvec or subcutaneous GM-CSF in patients with stage 3 and 4 melanomas. The trial showed monotherapy with laherparepvec significantly increases the durable response rate vs. therapy with GM-CSF alone (25.2% vs. 1.2%, respectively). It also improved the overall response rate (40.5% vs. 2.3%, respectively). The toxicity profile was similar in both treatment arms, with the majority of toxicities including grade 1 and 2 toxicities [55]. There are ongoing phase 3 trials examining the efficacy of combination therapy with laherparepvec and pembrolizumab in stage 3 and 4 melanomas. Earlier phase 2 trials appear promising.

100 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

Dendritic cells are a form of immune cell, which is the more powerful antigen-presenting cell. The cells circulate in their inactive state in the body circulation. When they are exposed to a danger signal, they become activated antigen-presenting cells. They facilitate immune responses in the lymphoid tissue, causing the naïve T-cells to differentiate into effector T cells. DC cells facilitate activation of tumour immunity. They activate antigen-specific T cell responses in melanoma patients. Dendritic cell vaccines are activated dendritic cells containing tumour antigens. Dendritic cells are not advisable as monotherapy in the treatment of advanced melanoma. However, there are promising results when DC viruses are combined with ipilimumab. It is postulated that the immune system is more potent in stage 3 vs. stage 4 melanoma. Dendritic cells show some promise in stage III melanoma. However, phase 3 trials are pending. The safety profile of DC vaccines is favourable when compared with checkpoint inhibitors [56].

In the advent of targeted therapies, chemotherapy is no longer deemed a first-line therapy for metastatic cutaneous melanoma in the latest ESMO guidelines [2]. However, in the recent past, chemotherapy was an important therapeutic strategy for palliation. Examples of chemotherapeutic agents employed in melanoma include dacarbazine, temozolomide, nab-paclitaxel, paclitaxel, cisplatin, carboplatin, and vinblastine. The only chemotherapy agent approved by the FDA

**3.4. Dendritic cells**

**4. Chemotherapy**

In conclusion, immunotherapy and targeted therapy in the form of BRAF/MEPK inhibitors form the backbone of therapy for metastatic melanoma. The optimal agents remain under considerable debate. Chemotherapy has been relegated to second-line therapy. Future guidelines will likely reflect this new research.

In conclusion, the mainstay treatment for managing melanoma remains surgery if feasible. There are several adjuvant therapies such as anti-PD1 therapies, CTLA4 inhibitors and BRAF/ MEK inhibitors that may play a useful role as adjuvant therapies in high-risk, stage 3 disease. The treatment strategies for advanced melanoma are evolving rapidly. Targeted therapies such as anti-PD1 therapies, CTLA4 inhibitors and BRAF/MEK inhibitors have become mainstay treatment. Further research must be carried out to determine the best regimen. Chemotherapy now only plays a role in rescue therapy.
