mRNA-Based Therapy for Melanoma
Melanoma is a life-threatening disease, also known as the deadliest skin cancer, caused by mutations in pigment-producing cells. Although many treatments for melanoma have been approved over the past few decades. Currently, there are no ideal treatments, as they can cause serious side effects and are not completely cured. Cancer immunotherapy is a revolutionized cancer therapy, providing more tolerable approaches over chemotherapy. mRNA-Based immunotherapy provides a new avenue for melanoma treatment and has unique advantages over conventional treatments. At present, mRNA-based drugs for melanoma treatment are in clinical trials, and the Food and Drug Administration (FDA) approval of mRNA-based drugs does not seem to be far away. Creative Biogene is a forward-looking research institute as well as a leading custom service provider in mRNA-based drug research and development (R&D). Our team is experienced in the customized synthesis of mRNA, mRNA optimization, and mRNA delivery system development. We are devoted to offering high-quality service and achieving the best outcome for our customers from all over the world.
Melanoma—the deadliest skin cancer
Melanoma, also redundantly known as malignant melanoma, is one of the most aggressive forms of skin cancer that develops from pigment-producing cells (melanocytes). In addition to predominantly located in the skin, melanoma can also be found in ears, eyes, oral mucous membranes and GI tract. Melanoma causes the most skin-related deaths worldwide, even though it accounts for less than 5% of all skin cancers. In the last decades, many different modalities have been developed to treat advanced melanoma, including chemotherapy, targeted therapy, immunotherapy, radiation therapy and combinations of therapies. However, these therapies are not reliable. During and after treatment, many patients suffer from severe side effects. There is a need to develop new approaches or combinations to fight against the disease.
mRNA-based drugs for melanoma
mRNA-4157/personalized cancer vaccine
To date, there are several mRNA drugs in trials as vaccination agents, including mRNA-4157, which aims to vaccinate patients against their tumors. In this mRNA-based therapeutic approach, a personalized cancer vaccine against a specific melanoma is generated according to the sequence information from the patient. Patient-specific mRNA-4157 encoding the twenty patient-specific epitopes (that might trigger a strong immune response) are produced and administered to the patient. This could trigger the adaptive immune response by induction of cytotoxic T cells and these T cells are able to specifically target cancer cells expressing the neoantigens. In addition, mRNA-4157 has been combined with immune checkpoint inhibitor Pembrolizumab for the treatment of melanoma. Since mRNA-based therapeutics activate a specific immune response (T cell response) against the tumor through over-presentation of tumor-specific antigens. The co-delivery of a checkpoint inhibitor is beneficial because it prevents inhibition of the checkpoint protein response to the T cells.
Fig1. The workflow for generating personalized cancer vaccine. (van Dülmen, M., et al, 2020)
mRNA encoding TriMix/ TriMix matured DC
Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) of the immune system and play an important role in preventing the human body from viruses and cancers. Therefore, Ex vivo therapy with transfected DCs is the most frequent strategy used for mRNA cancer vaccination. The TriMix technology builds on three mRNAs encoding immune-stimulating factors (CD40L, CD70, as well as caTLR4) to activate DCs. Among them, caTLR4 promotes the maturation of DCs and stimulates DCs to present different types of antigens to T cells. CD40L and CD70 ligand both act as co-stimulatory molecules and activate CD4 (T-helper lymphocytes) and CD8 (cytotoxic T-lymphocytes). In addition, TriMix mRNAs can be administered together with a specific mRNA coding for tumor-specific antigens for specific therapeutic applications. In a clinical trial, monocyte-derived dendritic cells are electroporated with antigen-encoding mRNA as well as TriMix-mRNAs and re-administered in the patient. In combination with ipilimumab (an anti-CTLA-4 monoclonal antibody), also called TriMixDC-MEL IPI treatment, results in robust CD8+ T cell responses in a meaningful portion of stage 3 and 4 melanoma patients, and obviously in patients with clinical response.
Fig2. Another approach uses three different mRNAs to activate dendritic cells (DCs) (TriMix matured DC, upper arrow) and consequently T cells. (van Dülmen, M., et al, 2020)
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References
- De Keersmaecker, B., et al. (2020). "TriMix and tumor antigen mRNA electroporated dendritic cell vaccination plus ipilimumab: link between T-cell activation and clinical responses in advanced melanoma." Journal for immunotherapy of cancer, 8(1).
- van Dülmen, M., & Rentmeister, A. (2020). "mRNA Therapies: New Hope in the Fight against Melanoma: Published as part of the Biochemistry series "Biochemistry to Bedside"."Biochemistry, 59(17), 1650-1655.
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