Neoantigen-based cancer vaccines: a mechanistic and clinical review of personalised melanoma immunotherapy

T-cell priming under appropriate conditions. Clinical data reflects this, with the mRNA vaccine mRNA-4157 (KEYNOTE-942) demonstrating a significant recurrence-free survival (RFS) benefit in the adjuvant setting. This efficacy, however, is contingent on the "hot" tumour microenvironment (TME) of melanoma; "cold" tumours like glioblastoma (GBM) and ovarian cancer (OvCa) present TME-specific barriers (e.g., the Blood-Brain Barrier, immune exclusion) that demand distinct, combination-based vaccine strategies. This review deconstructs this heterogeneity and defines the primary bottlenecks to broad clinical adoption: (1) the need to bridge the "validation gap" by correlating AI prediction accuracy with clinical outcomes; (2) the formidable economic and logistical barriers, including a clinically vulnerable 8-16 week manufacturing wait that poses psychological and clinical risks to patients; and (3) navigating adaptive regulatory pathways for "n-of-1" therapeutics. The field awaits the pivotal Phase III clinical trial of V940-001 (NCT05933577), whose timeline has been extended to 2029. This reflects the logistical and biological complexities inherent in developing personalised vaccines, highlighting challenges in both manufacturing and subject recruitment. These remain key obstacles impeding the widespread clinical application of such vaccines.