Neoantigen-Based and mRNA Therapeutic Cancer Vaccines: Clinical Status and Practical Bottlenecks

Abstract

Therapeutic cancer vaccines seek to generate or expand adaptive immune responses against malignant cells, potentially complementing treatments that remove or reduce tumour burden. This narrative review examines personalised neoantigen vaccines and mRNA vaccine platforms through representative clinical studies and research on barriers to translation. These approaches overlap: neoantigens define the molecular targets, whereas mRNA provides one means of delivering them. Early studies in melanoma, glioblastoma and pancreatic cancer demonstrate that vaccination can induce mutation-specific T cells, sometimes with sustained memory. Randomised phase 2 evidence in resected high-risk melanoma provides a more direct signal of clinical benefit when an individualised mRNA vaccine is added to pembrolizumab, with supportive long-term follow-up. Nevertheless, most other studies remain small, uncontrolled or confounded by concurrent treatment. Three connected bottlenecks limit wider application. Predicted peptide binding does not establish natural antigen presentation or tumour recognition; immune exclusion and inhibitory mechanisms can prevent vaccine-induced cells from controlling disease; and individualised development requires timely tissue processing, antigen selection, manufacturing and quality assurance. Improvement therefore requires more than a stronger immune assay result. Priorities include clinically justified combinations with checkpoint blockade, prospectively validated antigen-selection methods, and manufacturing processes evaluated by the proportion of eligible patients who receive treatment on time. Shared mutation vaccines may reduce individual production requirements but apply only to biologically defined patient groups. The field has progressed from proof of immunogenicity towards evidence of clinical activity, while broad implementation still requires confirmatory trials, reliable delivery and transparent assessment of safety, cost and access.