intismeran autogene (mRNA-4157)

This review synthesizes recent advances in biomimetic and personalized nanovaccine design, highlighting clinical progress in lipid nanoparticle (LNP)-based vaccines such as BNT111 and mRNA-4157, emerging innate immune adjuvants including Toll-like receptor (TLR) and stimulator of interferon genes (STING) agonists, and rational combination strategies with immune checkpoint blockade. Key safety and quality consideration including immunotoxicity, off-target immune activation, and batch heterogeneity are critically evaluated alongside emerging engineering solutions. Finally, future directions integrating AI-guided neoantigen prediction, modular microfluidic manufacturing, and multi-omic biomarker frameworks are discussed to accelerate next generation cancer nanovaccine translation.

Most trials focused on Stage III/IV patients (91.1%): key trials showed mRNA-4157 + pembrolizumab reduced recurrence/death risk by 49% in resected melanoma, and herpes simplex virus RP1 + nivolumab achieved 58.3% objective response rate (ORR) in ICI-resistant patients. However, challenges include tumor heterogeneity, immunosuppressive tumor microenvironment (TME), inefficient delivery, geographical R&D imbalance, and low Phase III conversion. Interdisciplinary collaboration, international multicenter trials, optimized clinical design (e.g., early-stage patient enrollment), and policy support are needed to advance their clinical translation.

Ongoing combination strategies include MEK inhibition with type II RAF inhibitors (naporafenib plus trametinib in phase III trial), ERK1/2 or ERK5 inhibitors, PI3K/mTOR pathway blockade, or CDK4/6 inhibition. Additional investigational approaches include mutation-specific RAS inhibitors (G12C inhibitors already approved for other cancers), NRAS-specific or pan-RAS inhibitors (daraxonrasib in phase III trial for other cancers), targeted protein degradation, RAS-directed peptide and mRNA vaccines (mRNA-4157). NRAS Q61K-derived neoepitopes bound to HLA-A*01:01 have been recognized as immunogenic, suggesting that mutation-specific immunotherapies could represent a promising future strategy. In conclusion, the advent of promising and emerging therapies is set to transform the management of RAS-driven melanoma, making a personalized, biomarker-informed treatment strategy essential for optimizing patient outcomes.

P1/2, N=230, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

P2, N=180, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

P2, N=267, Active, not recruiting, ModernaTX, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Sep 2029 --> Nov 2032 | Trial primary completion date: Sep 2029 --> Nov 2032

P1, N=242, Active, not recruiting, ModernaTX, Inc. | Recruiting --> Active, not recruiting

P2, N=180, Not yet recruiting, Merck Sharp & Dohme LLC

Clinical milestones, including the randomized phase IIb KEYNOTE-942, show that adding the personalized neoantigen vaccine mRNA-4157 (V940) to pembrolizumab prolonged recurrence-free survival versus pembrolizumab alone (HR 0.561, 95% CI 0.309-1.017; 18-month RFS 79% vs. 62%), with the ASCO 3-year update reporting 2.5-year RFS 74.8% vs. 55.6% and sustained distant metastasis-free survival benefit in resected high-risk melanoma. Parallel preclinical studies highlight the potential of multifunctional platforms co-delivering cytokines or innate agonists to reshape the tumor microenvironment and achieve durable systemic immunity. As artificial intelligence drives epitope selection and modular manufacturing accelerates personalization, mRNA vaccines may have the potential to transition from adjuncts to main therapies in melanoma and beyond.

P2/3, N=46, Active, not recruiting, Merck Sharp & Dohme LLC | N=1012 --> 46

Early clinical trials suggest pembrolizumab and mRNA-4157/V940 may boost T cell-mediated cancer killing. Knowing the status and problems of melanoma therapeutic mRNA cancer vaccines in clinical trials is critical. In this chapter, we have focused on preclinical and clinical advances that have revealed mRNA melanoma vaccine manufacturing issues and solutions.

P1, N=242, Recruiting, ModernaTX, Inc. | Trial completion date: Jun 2025 --> Aug 2027 | Trial primary completion date: Jun 2025 --> Aug 2027