Characterization and monitoring of antibody drugs
Melanoma is an aggressive and highly lethal disease, prone to metastasize to the lungs and even throughout the body. Currently, the optimal treatment modalities for advanced melanoma encompass targeted chemotherapy, oncolytic viruses (OVs) application, and immune checkpoint inhibition (ICI). In the context of primary melanoma treatment, OV therapy holds great promise. OV replication can induce remodeling of tumor cell lysis and microenvironment (TME). It also promotes the repolarization and recruitment of immune cells, thereby triggering secondary immune-mediated oncolysis.
Introduction to Melanoma and The Structural Elements of The Skin
The skin is divided into three layers: the epidermis, the dermis, and the hypodermis.
- Epidermis: The epidermis typically consists of four layers: the stratum basale, the stratum spinosum, the stratum granulosum, and the stratum corneum.
- Dermis: Its cellular components include fibroblasts, macrophages, and adipocytes.
- Hypodermis: The hypodermis is the deepest layer, which is composed of the main branches of the skin circulatory system, sweat glands, and adipose tissues that produce vitamin D and triglycerides.
Melanoma is induced by the transformation and unregulated proliferation of melanocytes in the basal layer of the skin. It can arise not only in the skin but also in the eyes, mucous membranes, and other cutaneous-related areas. Long-term ultraviolet exposure and a family history of the disease are associated risk factors.
Melanoma comprises four principal subtypes: superficial spreading melanoma, lentigo malignant melanoma, acral lentiginous melanoma, and nodular melanoma.
Major Mutations and The Targeted Therapy in Melanoma Development
The main mutations that occur during melanoma development include BRAF mutations. Additionally, NRAS mutations, TERT promoter mutations, and the activation of the MAPK signaling pathway can be targeted for therapeutic intervention.
| Target | Mutation | Targeted Therapy |
|---|---|---|
| BRAF Mutations | A point mutation at codon 600 results in the substitution of glutamate for valine. Mutated BRAF impacts tumor survival and proliferation via downstream MAPK effector proteins and is likewise linked to augmented tissue invasion, cell migration, metastasis, and immune evasion. | BRAF inhibitors (BRAFis) such as vemurafenib and dabrafenib. |
| NARS Mutations | NRAS mutations are present in approximately 20% of wild-type BRAF melanomas. Results in defective GTPase activity and accumulation of RAS-GTP. Melanomas carrying NRAS mutations tend to be associated with more aggressive tumors and poor health. | siRNAs represent an alternative means for targeting NRAS-mutated melanomas. This strategy has been verified in pre-clinical models. However, owing to the instability of nucleic acids in the bloodstream, their delivery poses a substantial challenge. |
| Activation of MAPK pathway | BRAF-mutated melanomas activate MAPK effector proteins, affecting tumor survival. Melanomas with NRAS mutations are dependent on CRAF signaling. | Targeting downstream components of the MAPK signaling pathway with MEK inhibitors reduces drug resistance. |
| TERT promoter mutations | TERT mutations might be directly triggered by UV-induced damage. This creates binding motifs for ETS transcription factors, which enhance TERT transcriptional activity by a factor of two to four. The elevated transcriptional activity essentially leads to augmented telomerase production, thereby giving rise to immortalized, transformed melanocytes. |
Oncolytic virus therapy for melanoma
- T-VEC
Talimogene laherparepvec (T-VEC), a modified attenuated virus, is administered via intratumoral injection to stimulate the immune system in patients with postoperative recurrent melanoma. Fatigue is a common side effect, and in some cases, it may be associated with the risk of infection and autoimmune reactions. The combination of T-VEC and PD-1 antibodies demonstrates a remarkable effect in the treatment of malignant melanoma. Currently, this combination has also shown promising progress in the treatment of advanced sarcoma.