Introduction

Cancer immunotherapy has revolutionized oncology, with approaches such as Immune Checkpoint Inhibitors (ICIs), adoptive T cell therapy, and Chimeric Antigen Receptor (CAR) T cells providing unprecedented durable responses in subsets of patients. However, these therapies are not universally effective, and many patients develop resistance or fail to respond altogether. Against this backdrop, neoantigen vaccines have emerged as a promising strategy to generate robust and durable antitumor immunity by harnessing the patientâ??s own unique tumor mutations. Neoantigens are tumor-specific peptides that arise from somatic mutations, producing novel protein sequences that are absent in normal tissues. These mutation-derived epitopes can be presented by Major Histocompatibility Complex (MHC) molecules on tumor cells, making them highly immunogenic and ideal targets for T cellâ??mediated attack. Unlike shared tumor-associated antigens, neoantigens carry minimal risk of inducing autoimmunity because of their tumor-restricted expression. Neoantigen vaccines represent the frontier of personalized immunotherapy, offering the possibility of designing bespoke vaccines tailored to the mutational landscape of an individualâ??s tumor [1].

Description

The scientific rationale for neoantigen vaccines rests on the fundamental principle of immunological recognition. Somatic mutations in cancer cells give rise to aberrant proteins, some of which undergo proteasomal degradation to generate peptides capable of binding to MHC molecules. When displayed on the tumor cell surface, these peptides can be recognized as â??non-selfâ? by T Cell Receptors (TCRs), initiating an immune response. Unlike overexpressed self-antigens such as Carcinoembryonic Antigen (CEA) or HER2, which are often subject to central tolerance and can lead to autoimmunity, neoantigens are completely novel to the immune system. This makes them ideal vaccine targets with high tumor specificity and reduced toxicity. The process of developing a neoantigen vaccine is highly individualized. First, tumor and normal tissue samples from the patient are subjected to Whole-Exome Sequencing (WES) and RNA sequencing to identify nonsynonymous mutations. Advances in Next-Generation Sequencing (NGS), bioinformatics pipelines, and vaccine delivery platforms have accelerated their development [2].

One of the key strengths of neoantigen vaccines is their ability to stimulate polyclonal T cell responses directed against multiple tumor-specific targets simultaneously. This multi-epitope approach reduces the likelihood of immune escape through antigen loss variants and enhances the breadth of immune coverage across heterogeneous tumor populations. Furthermore, because neoantigens are unique to each tumor, they can serve as â??fingerprintsâ? of malignancy, enabling the immune system to distinguish cancer cells from normal tissues with exquisite precision. Several vaccine delivery platforms have been explored to maximize immunogenicity and durability. Peptide-based vaccines offer simplicity and safety, particularly when combined with strong adjuvants such as toll-like receptor agonists. RNA vaccines, propelled into the spotlight during the COVID-19 pandemic, offer rapid manufacturing, scalability, and the ability to encode multiple epitopes within a single formulation. DNA vaccines and viral vectors provide alternative approaches with enhanced antigen expression and cross-presentation capabilities. Dendritic cellâ??based vaccines, though logistically complex, directly exploit the bodyâ??s most potent antigen-presenting cells for optimal T cell priming. Each platform carries distinct advantages and challenges, with ongoing clinical trials seeking to identify the most effective modalities [3].

The clinical translation of neoantigen vaccines has gained momentum over the past decade. Early-phase trials in melanoma, glioblastoma, and non-small-cell lung cancer have demonstrated feasibility, safety, and encouraging immunogenicity. In a landmark study, personalized neoantigen vaccines induced strong polyfunctional T cell responses in melanoma patients, with evidence of long-term memory formation and delayed tumor recurrence. In glioblastoma, a notoriously immunologically â??coldâ? tumor, neoantigen vaccines have successfully elicited immune infiltration into the tumor microenvironment, suggesting potential synergy with other immunotherapies. NSCLC trials have reported prolonged progression-free survival in patients receiving vaccines in combination with immune checkpoint inhibitors, highlighting the potential for combinatorial regimens. While checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies release the brakes on existing T cell responses, they require a pre-existing repertoire of tumor-reactive T cells to be effective. In patients with low tumor mutational burden or poorly immunogenic tumors, checkpoint blockade alone may be insufficient [4,5].

Conclusion

Neoantigen vaccines epitomize the promise of personalized medicine in oncology, offering the ability to tailor immunotherapy to the unique mutational landscape of each patientâ??s tumor. By targeting tumor-specific epitopes with high immunogenic potential, these vaccines elicit robust, precise, and durable antitumor responses with minimal off-target toxicity. Advances in sequencing, computational biology, and vaccine delivery platforms have brought neoantigen vaccines from theoretical concept to clinical reality, with early trials demonstrating safety, feasibility, and meaningful clinical benefit. Their integration with checkpoint inhibitors, adjuvant therapy strategies, and combination regimens further highlights their transformative potential. While challenges related to tumor heterogeneity, immune evasion, and manufacturing logistics remain, ongoing innovations are rapidly addressing these barriers. With the continued convergence of genomics, artificial intelligence, and immunoengineering, neoantigen vaccines are poised to become a central pillar of cancer immunotherapy.

Acknowledgement

None.<.p>

Conflict of Interest

None.

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