A personalized vaccine based on mRNA technology (called mRNA-4157) could cure deadly melanoma when given with an immunotherapy drug (Keytruda®, also known as pembrolozumab) that had already been approved for treating several types of cancer1-4. This is the same technology that was used to make the Covid-19 vaccines from Moderna/Lonza (mRNA-1273) and Pfizer/BioNTech (BNT162b2). The self-replicating mRNA codes for proteins that are made by either the virus that causes Covid-19 or the specific type of melanoma cells in cancer patients. They have a modified nucleic acid (1-methyl-pseudouridine) that increases the translation of mRNA into the antigenic proteins and helps avoid harmful over-activation of the innate immune system.
Both vaccines are encapsulated with lipid nanoparticles that protect the mRNA from being degraded in the blood or liver before it reaches the virus or cancer cells. Moreover, Moderna and Pfizer continue to develop vaccines that will hopefully cure other types of cancer. These vaccines target tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs). Biopsies collected from a patient’s tumor samples can be used to find and target patient-specific TAAs and TSAs. They stimulate cell-mediated immune responses that are capable of clearing or reducing the size and metastasis of tumors. This personalized treatment avoids harmful side effects seen with older drugs that were given to treat cancer, with limited success. At the same time, Keytruda® helps the patient’s immune system do a better job of recognizing cancer cells and eliminating them.
A healthy, balanced immune system constantly surveys the body and eliminates cells that it recognizes as foreign – be they infected with a virus or have become cancerous. However, it’s important that one’s immune system not become too overactive and attack healthy, uninfected cells and tissues. To do this, it must be able to distinguish between self and non-self. That is, our own cells have specific proteins on their surface that our immune cells recognize as self. They are not destroyed.
So, the immune cells that are present in malignant tumors have been identified and characterized. This includes immune modulators and mechanisms, such as the programmed cell death-1 (PD-1 or PD-L1) checkpoint inhibitors that could be targeted therapeutically5. The PD-1 (or PD-L1) receptor (also known as CD279) is on the surface of activated T-cells. It is an important part of our natural protection against cancer through a cancer immunity cycle. This cycle enables the immune system to have an anti-cancer response and kill cancer cells. First, dendritic cells capture tumor cells that have mutated cell surface antigens.
Second, the dendritic cells prime T cells with the tumor antigen, thus activating cytotoxic T cells. Third, the activated T cells travel to the tumor and infiltrate its environment. Fourth, the activated T cells recognize and bind to the cancer cells. Fifth, the bound effector T cells release cytotoxins, which induce apoptosis in the target cancer cells. Finally, dying cancer cells release more tumor-associated antigens, which propagate the immunity cycle further and kill more cancer cells. However, this response must be properly regulated to maintain the balance between appropriate recognition and destruction of tumors and the inappropriate overstimulation of immune responses, that can lead to damage to normal, healthy cells and tissues. The PD-1 (or PD-L1) signaling pathway is an essential part of this regulation.
The PD-L1 receptor is on the surface of activated T cells6. Its ligands, PD-L1 and PD-L2, are widely expressed on the surface of dendritic cells and other immune cells. PD-L1 and PD-L2 are immune checkpoint proteins that act as co-inhibitory factors. They can halt or limit the development of the T-cell response. The interaction between PD-L1 and PD-L2 with their cognate receptor ensures that the immune system is activated only at the appropriate time. This minimizes the probability of chronic autoimmune inflammation. However, tumor cells can exploit this immune-checkpoint pathway so they can evade detection and inhibit the immune response. The PD-L1 is frequently over-expressed on tumor cells or on non-transformed cells in the tumor microenvironment. PD-L1 on tumor cells can bind to PD-1 receptors on the activated T cells. This inhibits the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment.
Cancer immunotherapy aims to overcome the ability of cancer cells to resist the immune responses and to stimulate the body's own mechanisms that enable it to remain effective against cancer. Recently, monoclonal antibody therapies against PD1 and PD-L1 have shown promising results. This includes Keytruda®.
Even though Keytruda® by itself is successful in treating many patients with melanoma, not everyone responds as well. For those, a clinical trial was performed, in which the combination of Keytruda® and mRNA vaccine mRNA-41571-3. In that study, 78.6% of those who received the personalized vaccine and Keytruda® were free of cancer at 18 months. No serious side effects from the experimental vaccine have been reported. Common minor side effects include fatigue, injection site pain and chills.
A Phase 3 clinical trial will begin soon, and more are planned for treating other types of cancers, including lung cancer. According to the American Cancer Society, melanoma accounts for about 1% of all skin cancers, but it causes most skin cancer deaths. About 100,000 new melanomas will be diagnosed in the USA, and almost 8000 people will die from melanoma.
In the meantime, the FDA has approved a vaccine against RSV for people over 60, and the World Health Organization ended the Public Health Emergency of Concern caused by the Covid-19 pandemic due to high population-level immunity from infection, vaccination, or both7-8.
1 Moderna. Moderna and Merck Announce mRNA-4157 (V940), an Investigational Individualized Neoantigen Therapy, in Combination with KEYTRUDA® (Pembrolizumab), Demonstrated Superior Recurrence-Free Survival in Patients with High-Risk Stage III/IV Melanoma Following Complete Resection versus KEYTRUDA. 16 April, 2023.
2 Merck. Moderna and Merck Announce mRNA-4157 (V940), an Investigational Individualized Neoantigen Therapy, in Combination With KEYTRUDA® (pembrolizumab), Demonstrated Superior Recurrence-Free Survival in Patients With High-Risk Stage III/IV Melanoma Following Complete Resection Versus KEYTRUDA. 16 April, 2023.
3 Bafaloukos, D. et al. Evolution and progress of mRNA vaccines in the treatment of melanoma: future prospects. 13 March, 2023. Vaccines, volume 11, article 636.
4 Keytruda. A breakthrough immunotherapy that may help you face cancer.
5 Liu, J. et al. PD-1/PD-L1 checkpoint inhibitors in tumor immunotherapy. Frontiers in Pharmacology, Vol. 12, article 731798.
6 Qiu, Y. et al. Activated T cell-derived exosomal PD-1 attenuates PD-L1-induced immune dysfunction in triple-negative breast cancer. Oncogene Vol. 40, p. 4992-5001, 2021.
7 Middleton, J. FDA approves vaccine for adults 60 years and over. American Family Physician Blog, 8 May, 2023.
8 World Health Organization. Statement on the fifteenth meeting of the IHR (2005) Emergency Committee on the COVID-19 pandemic. 5 May, 2023.