**10. Oncolytic virus therapy**

vs. 11% [40]. There was no statistical difference in two contemporary oncology median overall survivals between the study arm with nivolumab, 15.7 months, vs. the comparator group with chemotherapy, 14.4 months. The limitation of the clinical benefit of nivolumab could be related to the fact that control group patients (40%) received pembrolizumab, when progressed during chemotherapy. Furthermore, the number of patients with elevated lactate dehydrogenase levels and brain metastases was imbalanced, favoring the chemotherapy [41]. Adverse events are less frequent in patients treated with nivolumab than in those treated with ipilimumab or chemotherapy [4, 10]. The most frequently observed adverse events included fatigue, pruritus, diarrhea, rash, and nausea. The most commonly observed immune-related adverse events were pruritus, rash, diarrhea, vitiligo, hypothyroidism, and elevated aminotransferase activities [42]. In the study of Pyo and Kang the effects of various immunotherapeutic agents and chemotherapy for unresected or metastatic melanomas were compared. They performed a network meta-analysis using a Bayesian statistical model to compare objective response rate of various immunotherapies from 12 randomized controlled studies. The estimated overall response rates of immunotherapy and chemotherapy were 0.224 and 0.108, respectively. The overall response rates of immunotherapy in untreated and pretreated patients were 0.279 and 0.176, respectively. In network meta-analysis, the odds ratios for overall response rate of nivolumab (1 mg/ kg)/ipilmumab (3 mg/kg), pembrolizumab (10 mg/kg) and nivolumab (3 mg/kg) were 8.54, 5.39 and 4.35, respectively, compared with chemotherapy alone. Their results showed that various immunotherapies had higher overall response rates rather than chemotherapy alone [43].

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

Except immunological checkpoint blockades the approach of *adoptive T cell therapy* seems to be a highly promising in use against cancer including melanoma. The ability of T cells to specifically lyse tumor cells and secrete cytokines to recruit and support immunity against cancer make them an attractive proposition for therapy. Since the first idea in 1989 to genetically redirect T cells, a lot of experiments have been performed. Recent methods of generating tumor-specific T cells include the genetic modification of patient's lymphocytes with receptors to endow them with tumor specificity. These T cells are then expanded *in vitro* followed by infusion of the patient in adoptive cell transfer protocols. Genes used to modify T cells include those encoding T-cell receptors and chimeric antigen receptors. Several trials with gene-modified T cells are ongoing and some remarkable responses have been reported [44]. In fact, current adoptive T cell therapy response rates are 80–90% for hematological malignancies and 30% for metastatic melanoma refractory to multiple lines of therapy. Although these results are encouraging, there is still much to be done to fulfill potential of adoptive T cell therapy, specifically with regard to improving clinical efficacy, expanding clinical indications

Melanoma vaccines have the goal to induce long lasting immunity against melanoma to prevent the development of metastases. However, melanoma cells express many different tumorassociated antigens. Ideally, vaccines need to contain all these different tumor-associated antigens for antigen-presenting-cells (APC) to induce an adequate immune response [46].

and reducing toxicity [45].

**9. Cancer vaccines**

Over the past several years, oncolytic viruses for treating various cancers have been investigated. Oncolytic viruses play a role in cancer vaccination because antigen-specific immunity is effectively evoked against components released by destroyed cancer cells due to virusinduced production of type I interferon. The effects of oncolytic virus therapy are mediated not only by direct cell disruption, but also by indirect induction of cancer-specific immune responses [48].

Oncolytic viruses selectively replicate within and lyse cancer cells without damaging normal cells. On October 27, the FDA approved the first oncolytic virus therapy, *talimogene laherparepvec (Imlygic™, T-VEC)*. The agency approved T-VEC for the treatment of some patients with unresectable cutaneous, subcutaneous, and nodal lesions in melanoma recurrent after initial surgery [50]. T-VEC is a modified herpes simplex virus, type 1 (HSV-1) that has undergone genetic modifications to promote selective tumor cell replication, while reducing viral pathogenicity and promoting immunogenicity. T-VEC improves overall response rate and durable response rate as a single agent, shows promise in combination therapy with immunotherapy, and is well tolerated. Ongoing trials will determine if T-VEC has a role in early treatment or in combination therapy for melanoma or other malignancies, such as hepatocellular carcinoma, metastatic liver tumors, advanced non-central nervous system tumors, breast cancer, pancreatic cancer, Merkel cell carcinoma, head and neck cancer, sarcoma, lymphomas. In a Phase I study, T-VEC has been combined with ipilimumab or pembrolizumab, with promising results without overlapping toxicities. The results of larger studies are awaited to further delineate T-VEC's place with combination therapy [51].

Protein Kinase (MAPK) cascade, which modulates cell growth and proliferation. This pathway is activated by binding of the extracellular physiological growth factor to its receptor. Conformational change of the receptor leads to the activation of RAS protein (GTP-binding), which activates RAF protein, which activates other kinases MEK and ERK. This pathway may be activated by mutation of specific proteins, including BRAF [52]. It is reported that 40–60% of melanomas have a mutation of the gene leading to the pathological-activated signaling pathways and to uncontrolled growth of malignant transformed cells [53]. The most common gene mutations are V600E or V600K known as an amino acid substitution at position 600 in BRAF, from a valine (V) to a glutamic acid (E) or to a lysine (K), respectively. In the structure of protein kinases there is a DFG motif, which is a highly specific site for interaction with kinase inhibitors. It contains Asp (D), Phe (F) and Gly (G) and exists in a conformational active or inactive state. Just the knowledge in this field has led to the development and screening of new selective inhibitors of BRAF and MEK (**Figure 2**) [54]. Targeted therapy is associated with improved clinical benefit; however, the mechanism of resistance often varies and includes

Possibilities for the Therapy of Melanoma: Current Knowledge and Future Directions

http://dx.doi.org/10.5772/intechopen.70368

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*Vemurafenib* (Zelboraf® tablets, Roche) is the first selective inhibitor of BRAF developed by Plexxikon and approved by FDA in 2011 (**Figure 3**). It leads to a rapid, and sometimes the complete remission of the disease in patients with a mutated BRAF V600E. A clinical study on 675 respondents treated with vemurafenib, 960 mg twice daily, demonstrated survival of 6 months in 84% of patients versus 64% of patients treated with dacarbazine. Despite significant benefit in the treatment, there were new challenges identified – the development of resistance to reactivation of MAPK signaling and growth of keratoacanthomas and squamous cells. The most common adverse events were headache, joint pain, fatigue, skin hyperkerato-

*Dabrafenib* (Tafinlar® capsules), developed by GlaxoSmithKline (**Figure 3**), selectively inhibits BRAF ValGlu [57]. It is a thiazole derivative, which binds to the ATP binding site of BRAF kinase. It has a shorter half-life than vemurafenib (5.2 h versus 50 h). In 2009, first clinical studies in

sis and 6% of the patients experienced a squamous cell carcinoma [56].

**Figure 3.** Chemical structures of vemurafenib, dabrafenib, trametinib, and selumetinib.

activation of alternative signaling pathways [55].

**12. BRAF inhibitors**
