Injecting hope into skin cancer treatment: The promise of melanoma vaccines

While surgery is still the mainstay treatment for melanoma, a type of deadly skin cancer, other therapies like checkpoint inhibitors, generally used for later-stage or recurrent melanoma, have revolutionized the treatment paradigm in the last few years, bringing survival rates up. Now, melanoma vaccines are also gaining traction in the clinic and could soon become a viable and effective treatment option, particularly when used in combination with other cancer drugs.  

Melanoma develops from melanocytes, the cells that produce pigment in the skin. It is characterized by the uncontrolled growth of these cells, often appearing as a new mole or a change in an existing mole. Although melanoma is much less common than other skin cancers, like basal cell carcinoma and squamous cell carcinoma, it is more likely to grow and spread if left untreated, and when this happens, it can be fatal.  

Nevertheless, there is hope on the horizon, as personalized mRNA vaccines have made great strides since COVID-19 and are now being tested as cancer vaccines, with the technology proving to be extremely promising for the treatment of melanoma.  

Melanoma mRNA vaccines: Clinical trial candidates to keep an eye on 

There are currently two leading candidates in the melanoma mRNA vaccine race: Moderna and Merck’s mRNA-4157 (V940) and BioNTech’s BNT111. 

Moderna and Merck’s mRNA vaccine mRNA-4157 could be a game-changer in melanoma treatment 

Famed for its Spikevax mRNA vaccine against COVID-19, Moderna is a key player in mRNA therapeutics. So, it is perhaps no surprise that the company is now leading the race to have its mRNA vaccine for melanoma approved, with a helping hand from multinational giant Merck, whose renewed oncology strategy has pivoted its focus toward a more multimodal, diverse pipeline, where Moderna’s mRNA-4157 slots in very nicely indeed.  

The vaccine candidate works by delivering mRNA wrapped in lipid nanoparticles into cells, instructing them to make a protein, which, in this case, involves up to 34 tumor neoantigens (foreign proteins that are absent in normal tissues, but can arise from tumors through various mechanisms) per patient. Essentially, this means that the vaccine teaches the immune system to recognize 34 different things that are unique to this particular cancer, ultimately improving the chances of success. 

Being tested in combination with Merck’s blockbuster checkpoint inhibitor Keytruda, which loses patent protection in 2028, mRNA-4157 has produced impressive results in clinical trials so far. In June 2024, Moderna and Merck reported that, after two and a half years, melanoma patients who received the combination therapy had an overall survival rate of 96%, compared to 90.2% with Keytruda alone. Additionally, the combination reduced the risk of recurrence or death by 49% and the risk of distant metastasis or death by 62% compared to Keytruda alone.  

The melanoma vaccine is currently being tested in a phase 3 study in people with high-risk melanoma, with a primary completion date of October 2029.  

Merck and Moderna have also initiated a phase 3 study of the candidate in non-small cell lung cancer (NSCLC), phase 2 studies in patients with renal cell carcinoma and urothelial carcinoma, and a phase 2/3 study for cutaneous squamous cell carcinoma. 

BioNTech’s mRNA vaccine BNT111 pairs up nicely with Regeneron’s checkpoint inhibitor  

BioNTech, also a well-known player in the vaccine space, is investigating its mRNA candidate BNT111 in a phase 2 trial for advanced melanoma. Like Moderna, the company has also teamed up with a pharma giant, Regeneron, to test BNT111 in combination with Regeneron’s Libtayo.  

BNT111 is a vaccine that encodes a fixed set of four non-mutated melanoma-associated antigens – NY-ESO-1, MAGE-A3, tyrosinase, and TPTE – with the aim of triggering T-cell responses against these antigens. As more than 90% of patients with cutaneous melanomas express at least one of the antigens, triggering responses against them could reenergize anti-cancer attacks in patients who do not respond to single-agent checkpoint inhibitors. 

In July 2024, BioNTech announced positive topline results from its phase 2 study of BNT111 in combination with Libtayo. The trial met its primary endpoint with data demonstrating statistically significant improvement in the overall response rate in patients treated with BNT111 in combination with Libtayo compared to historical control data.  

At the time of these results, the phase 2 trial was set to continue as planned to further assess its secondary endpoints, which were not ready at the time of the primary analysis. The study has a completion date of December 2025.  

BNT111 received orphan drug designation from the U.S. Food and Drug Administration (FDA) in September 2021, as well as fast track status in November 2021, which the company said underlines the potential of its FixVac vaccine platform to address the current treatment challenges of melanoma. 

DNA vaccines for melanoma: Scancell advances iSCIB1+ through the clinic  

Scancell, a British biotech developing off-the-shelf active immunotherapies to generate safe and long-lasting tumor-specific immunity, recently announced more positive data from its ongoing phase 2 trial of its DNA vaccines, SCIB1 and iSCIB1+, in combination with checkpoint inhibitors in patients with advanced unresectable melanoma.  

The study involved patients in cohorts one and three receiving SCIB1 or iSCIB1+, respectively, in combination with Bristol Myers Squibb’s checkpoint inhibitors Opdivo and Yervoy. The combined overall response rate for evaluable patients in these cohorts was 68.6%, with a disease control rate of 88% and a complete response rate of 17.9%.  

Although both of Scancell’s vaccines achieved similar results, the company decided to select iSCIB1+, which is essentially just a modified version of SCIB1 intended for enhanced potency, for further development due to the fact that it is suitable for use in around 80% of patients compared to just 35% to 40% for SCIB1.  

Further updates from Scancell’s phase 2 trial are scheduled for later this year, with the company planning to publish progression-free survival and early overall survival data in the fourth quarter. 

Evaxion Biotech pushes forward with personalized melanoma vaccine EVX-01

Evaxion Biotech, meanwhile, is developing a personalized peptide-based cancer vaccine intended for first-line treatment of multiple advanced solid cancers. It is currently being tested in a phase 2 trial for the treatment of advanced melanoma. The vaccine, designed with the company’s AI-Immunology platform, is tailored to target the unique tumor profile and immune characteristics of each patient, ultimately engaging the patient’s immune system to fight off cancer by mounting a targeted response against tumors. 

In April, Evaxion reported data from its phase 2 trial, which is investigating EVX-01 in combination with Merck’s Keytruda, showing that 80% of EVX-01 vaccine targets triggered a tumor-specific immune response. The company said that this is a substantially higher frequency than what has been reported for other similar vaccine candidates.  

Subsequently, in May, Evaxion said it had dosed the first patient in its one-year extension of the ongoing phase 2 trial, which will further explore the full potential of EVX-01 as a possible new and innovative treatment for advanced melanoma, particularly its long-term clinical and immune benefits.  

Furthermore, patients entering the one-year extension will receive two additional EVX-01 doses as monotherapy. In the first two years of the trial, the melanoma vaccine was administered in combination with anti-PD-1 therapy. But, with checkpoint inhibitor treatment restricted to a two-year duration, the extension phase provides an opportunity to evaluate the benefits of EVX-01 monotherapy, which could position the vaccine as a potential standalone treatment for advanced melanoma. 

New technologies related to melanoma vaccines

• AIM2 siRNA Adjuvant for Melanoma Therapy – UMass Chan Medical School
• Biopolymer Cancer Vaccine Technology – Griffith University
• Nanoparticle Therapeutic Vaccines for Cancer Treatment – University of California, Irvine

Do vaccine combination therapies hold the key to treating melanoma? 

As can be seen with the aforementioned vaccine trials, combination therapies involving a cancer vaccine and checkpoint inhibitors, which have also been groundbreaking for cancer treatment, are proving popular for the treatment of melanoma and other types of cancer.  

In a previous interview with Labiotech, Thomas Marron, director of the Early Phase Trials Unit at the Tisch Cancer Institute and associate professor of medicine at the Icahn School of Medicine at Mount Sinai, commented on Moderna’s vaccine trial, saying: “I believe the combination is key to the efficacy we are seeing, as the vaccine teaches the immune system what to recognize, but it is Keytruda that takes the brakes off the immune system and enables the strongest, most potent vaccinal response against the cancer. While cancer vaccines alone have been shown to work in some instances, the greatest benefit will come from combinatorial approaches such as this.” 

Whether used in combination with other drugs or on their own, what does seem clear is that mRNA technology is now leading the way when it comes to cancer vaccines. What’s more, the global mRNA vaccines market size is expected to grow from $6.01 billion in 2025 to $20.43 billion by 2032, exhibiting an incredible compound annual growth rate (CAGR) of 19.1% during the forecast period.  

And, if Moderna and Merck’s mRNA-4157 progresses successfully through phase 3 of clinical development, it might not be too long before we see the benefit of this technology for the treatment of melanoma.