On 26 July 2023, Moderna and Merck announced the launch of a phase 3 trial of their personalized vaccine against melanoma, mRNA-4157 (also known as V940), plus pembrolizumab (Keytruda), as combination therapy for high-risk patients who have undergone surgery. The trial aims to enroll 1,089 patients, all at stages IIb to IV, with a primary endpoint of post-surgical recurrence-free survival. Final results are due in 2029.

Patients who received mRNA-4157 and the anti-PD-1 drug pembrolizumab in the earlier 157-participant KEYNOTE-942 open-label phase 2 trial showed a decrease of 44% in the risk of post-surgical recurrence or death relative to the risk with pembrolizumab alone. The vaccine did not increase the frequency of immune-related side effects of pembrolizumab or serious adverse events of grade 3 or higher. The most common side effects in the treatment group were fatigue, injection-site pain and chills — the now well-established adverse effects of mRNA vaccines. On the basis of the phase 2 results, the combination therapy received breakthrough designation from the US Food and Drug Administration in February 2023. Data from the trial were presented at the American Association of Cancer Research meeting in April and at the American Society of Clinical Oncology in June, but the study has not yet been published.

An estimated 325,000 new cases of malignant melanoma were diagnosed worldwide in 2020. The clinical deployment of immune checkpoint inhibitors over the past 12 years has revolutionized melanoma treatment, and the 5-year survival rate in the USA now approaches 95%. However, the frequency of melanoma is increasing, particularly in lighter-skinned people, and for the minority of patients diagnosed with metastatic disease, the 5-year survival rate is 35%, although the introduction of immunotherapy has doubled the median survival time for these patients. The outlook for patients with metastatic melanoma was so bleak before the advent of immune checkpoint inhibitors that at the time of the landmark 2010 trial of ipilimumab (anti-CTLA-4), there was no approved standard of care, so the control group received a failed (but safe) peptide vaccine candidate: gp100.

mRNA-4157 is not a single drug, but is instead a personalized mRNA that encodes up to 34 different patient-specific neoantigens. In the phase 2 KEYNOTE-942 trial, the minimal number of target epitopes per patient was 9, and 91% of patients received mRNA encoding the full 34 epitopes. The vaccine’s manufacturing pipeline begins with sequencing of the genome of each patient’s tumor and healthy tissue. Moderna then uses a proprietary algorithm to identify promising tumor-specific mutations. The entire process, from sample collection to delivery of the lipid-nanoparticle-encapsulated mRNA, currently takes about 6 weeks, although Moderna CEO Stéphane Bancel says the goal is to bring the manufacturing time down to 30 days. The treatment course consists of up to nine intramuscular doses of the mRNA vaccine, one every 3 weeks, and nine intravenous infusions of pembrolizumab.

Moderna and Merck opted to kick off their joint clinical program in melanoma, as this cancer is known to be immunogenic and to respond to checkpoint inhibitors. The companies also intend to test the combination therapy against another checkpoint-inhibitor-responsive tumor type: non–small-cell lung cancer. Earlier this year, BioNTech published positive, but very preliminary, results of a personalized neoantigen mRNA vaccine for pancreatic cancer, a tumor type that until now had proven refractory to all forms of immunotherapy. BioNTech also has its own mRNA vaccine program for melanoma. Interestingly, BioNTech has shifted to unmodified RNA nucleotides for its anti-cancer vaccines, which may or may not be a factor in the effective priming of an immune response to an immunologically ‘cold’ tumor such as pancreatic cancer. This highlights how much the clinical success of lipid-nanoparticle-encapsulated mRNA vaccines has leapfrogged understanding of their adjuvanticity.

It is not clear why melanoma is so responsive to immunotherapy. The conventional explanation is that melanoma (and lung cancers linked to smoking) have a higher mutational load than that of most tumors. This explanation is appealing and fits conventional immunological wisdom. The fly in the ointment is that tumor mutational burden is an unreliable marker for responsiveness to immunotherapy. In the KEYNOTE-942 trial, patients with high tumor mutational burdens had responses to treatment similar to those of patients with low burdens. Part of the answer may lie in the quality, not the quantity, of the target neoantigens, although it is difficult to determine how much this contributes to mRNA-4157’s efficacy, because the epitope-selection algorithms are not public. In the BioNTech trial of pancreatic cancer, a key marker was the presence of primed T cells that recognized the vaccine antigens, as this is a solid baseline measure of on-target effect. That trial design also incorporated a clever control for general immunocompetence: measurement of responses to a vaccine against COVID-19. Hopefully, similar immunological data will be published for mRNA-4157.

Anti-cancer vaccines have a decades-long track record of failure, often after promising early results in small trials. Researchers have thrown every conceivable vaccine formulation at melanoma, from nonspecific vaccines such as bacillus Calmette–Guérin (directed against tuberculosis), to autologous or allogeneic cells, to tumor peptide and protein preparations. It is tempting to roll the dice and search ClinicalTrials.gov or PubMed for ‘melanoma vaccine’ + ‘kitchen sink’. For all the sound and fury, only one anti-cancer vaccine has ever been approved by the US Food and Drug Administration: sipuleucel-T for prostate cancer, in 2010 — a cellular immunotherapy with minimal survival benefits. The mRNA vaccine approach may be different, as it makes it feasible to target multiple patient- and tumor-specific neoantigens. Add to that the success of immunotherapy in blocking the immunoregulatory circuits that tumors often exploit, and effective vaccines may have finally arrived for some cancers.