Peptide vaccines have shifted the paradigm of therapeutic vaccination from a fixed, standard-of-care to a "tailored on demand" approach. Translating the unique tumor mutanome of a patient into synthetic peptides, a peptide-based vaccine educates the immune system to see cancer as foreign and attack it while leaving normal tissues unharmed, avoiding the off-target toxicities of traditional cytotoxic cancer therapies. This modality is also elegant in its simplicity: instead of using full proteins or viral vectors, only the minimal immunologically active part of the target protein is used for the vaccine, minimizing off-target and non-functional antigen presentation, and enabling simpler manufacturing process. This position at the intersection of individualized immunotherapy, industrialized chemical synthesis and flexible regulatory pathways has made peptide vaccines the poster child for the reemerging field of personalized immunotherapy in the 21st century.
Fig. 1 Preparation and mechanism of peptide cancer vaccine.1,2
Peptides are the natural language of cancer vaccines and bridge the divide between the private codes spoken by cancer genomes and the common language of the immune system. Their small size gives them multiple unique advantages. For example, they are exogenous antigens, which means they can directly be loaded on MHC molecules without further intracellular processing and yet complex enough to present conformational epitopes to enable efficient T-cell recognition. In comparison to protein and whole-cell vaccines, the high level of precision with which peptides can be designed is a major advantage. Their amino acid sequence can be individually selected and optimized, for example, by maximizing HLA binding through specific anchor residues, editing non-essential sequences to remove potentially tolerogenic parts, and by introducing heteroclitic substitutions that further increase immunogenicity. In addition, peptides can be used as dosage-regulators, where for example peptide length, flanking amino acid residues and the attachment of lipid or carbohydrate residues, can be used to specifically drive the presentation of peptides towards either MHC-I or MHC-II presentation, and hence control if a cytotoxic, helper or regulatory phenotype should be induced. Peptides can also be easily combined with any vaccine delivery technology. Peptide antigens can, for example, be chemically modified with amphiphilic tails that self-assemble to nanoparticles, conjugated to cationic peptides that form covalent bonds with mRNA, or adjuvant that can covalently be linked to the peptide to form a single-molecule "vaccinosome". As such peptides, can not only serve as the antigen component, but can also be used to co-deliver adjuvants, checkpoint-blocking ligands, or metabolic modulators, directly into the antigen presenting cell. Finally, since they can be produced with almost any sequence in parallel, using solid-phase peptide synthesis, this enables rapid parallel epitope discovery pipelines that can be fueled by resected tumor samples and real-time bioinformatic monitoring to generate vaccine candidate peptides within weeks, which is not possible with biologically produced vaccines.
TSAs are the ideal targets of peptide vaccines. The vaccine can be thought of as a wanted poster containing a molecular photo of the tumor, from which the optimal epitopes (or faces) are cut out and presented to the immune system for maximal recognition. TSAs are usually the result of somatic mutations, frameshift insertions, or gene fusions that are absent from the germline and are much more tumor-specific than tumor-associated antigens. Thus, the immunological window is narrowed to a set of epitopes that are unique to the tumor cells, sparing normal cells. In addition, neoantigens can be patient-specific or even lesion-specific (private to individual metastases) within the same patient. Thus, individualized peptide synthesis can be performed in parallel with real time tumor genomic monitoring. In-silico predictions can now be validated with mass-spectrometry immunopeptidomics to ensure the candidate peptides are actually being presented on patient tumor cells. Furthermore, since peptide vaccines have a modular design, both clonal (truncal) mutations shared by all tumor cells, and sub-clonal private mutations that may potentially seed resistance to the immune response can be targeted in a single vaccine. Tumors would not be able to escape a response in this setting because, if an immune-resistant minor sub-clone that does not express one epitope emerges, the other epitopes will still be targets of the immune system. Since the production of peptides is temporally stable, new mutations that arise under therapeutic pressure can be added to the list of epitopes targeted in the vaccine, without having to re-produce all of the previously selected peptides.
Peptide vaccines do not simply display antigens; they optimize the entire immune synapse to ensure that T cells not only see the target, but are also equipped to destroy it. The first means of optimization is epitope optimization: changes to amino-acid sequences can enhance weakly immunogenic wild-type peptides to become heteroclitic peptides with increased affinity to MHC and duration of peptide–MHC complexes on the cell surface. In addition, flanking sequences can be optimized to include cathepsin-sensitive motifs to promote cleavage and efficient delivery of the epitope within the endosome to generate a sustained rather than transient pulse of epitopes. In addition to optimizing the peptide, formulation is key. Encapsulating peptides within pH-sensitive liposomes or polymeric nanoparticles not only protects them from proteolysis but also targets them to draining lymph nodes where naïve T cells are abundant. Toll-like receptor agonists co-encapsulated within the nanoparticles provide a danger signal that turns otherwise tolerogenic dendritic cells into strong stimulators. Signals are also temporally controlled through the kinetics of nanoparticle degradation: an initial burst of adjuvant licenses antigen-presenting cells, followed by a slow and sustained release of peptide to continuously engage the T cell synapse. Even more sophisticated designs have conjugated checkpoint-blocking antibodies or metabolic modulators to the peptide carrier to target immune-activating and immune-releasing signals to antigen recognition sites. Finally, by extending peptide length, epitopes can be cross-presented on both MHC-I and MHC-II to produce a coordinated CD8+ cytotoxic and CD4+ helper response that feeds forward in cytokine environments enriched in IL-2, IFN-γ and TNF-α. The result of this optimized immune synapse is a positive feedback loop in which T cells expand, acquire tissue-homing receptors, and differentiate into memory subsets for quick recall upon tumor re-encounter.
Advantages of peptide vaccines over other types of cancer vaccines include a more favorable safety profile. The simplicity of peptides relative to larger immunogens can avoid the disadvantages of such agents. For example, vaccines based on whole proteins or whole cells may contain many irrelevant epitopes, some of which may be self-antigens and lead to epitope spreading and off-target autoimmunity. Peptides typically only contain the 8–30 residues required for T cell recognition, reducing the overall antigenic diversity of the vaccine. The smaller size and relative homogeneity of peptides compared to proteins also reduces the chance of the immune response cross-reacting with healthy tissue. The risk of hypersensitivity reactions caused by either conformational epitopes or contaminating post-translational modifications is also reduced. Additionally, solid-phase peptide synthesis results in chemically defined products, which can be fully characterized by mass spectrometry, and are thus less likely to contain residual host-cell proteins or adventitious agents that can contaminate recombinant protein expression. The short half-life of unformulated peptides also has a safety advantage as they can be rapidly cleared from circulation within hours of administration if the need arises. If a peptide vaccine is depot-formulated with an adjuvant, the degradation of the peptide is still more rapid and predictable than that of a protein aggregate, allowing for more accurate dose de-escalation. In contrast to the repeated administration of proteins, there is less risk of developing neutralizing antibodies to a peptide vaccine due to the lack of intact protein structure.
Recent advances in cancer immunotherapy have led to the conceptualization that each tumor represents a dynamic target with a unique set of mutations; the development of personalized neoantigen vaccines has made this concept a clinical reality. The process generally involves whole genome sequencing of a patient's tumor, followed by in silico and in vitro identification of true neoepitopes, and lastly the production of either peptides or nucleic acids for expression of the set of tumor-specific mutations. Neoantigen vaccines can be tailored to these mutations at any timepoint, and as such, the vaccine is more of a dynamic entity than a fixed product, as it can be updated to reflect clonal shifts during treatment. The true beauty of this strategy, however, is that only the antigenic component of the neoantigenome is leveraged, so that only those portions of a tumor's mutational landscape that are immunologically active are included in the vaccine, preventing exposure to all irrelevant or possibly tolerogenic antigens. Further, vaccine formulation allows this defined neoantigen component to be combined with a delivery platform, adjuvant, and/or checkpoint inhibitor that can be used to dictate spatial and temporal presentation in lymph nodes. This technology has the potential to make cancer treatment truly personalized.
A rational approach to identify tumor-specific antigens starts from the careful sampling and high-coverage whole-exome sequencing of normal and tumor tissue to identify somatic single-nucleotide variants (SNVs), insertions/deletions (indels), splice-junctions and fusion genes. Sequencing data is filtered using computational methods to differentiate somatic mutations from germline variations and sequencing errors, prioritizing mutations which are expressed at the RNA level, as determined by RNA-seq, and presented on HLA molecules on tumor cells, as determined by integration of data from mass-spectrometric immunopeptidomics in a proteogenomic analysis approach. Immunological datasets are used to computationally predict HLA binding, TCR contacts and potential immunogenicity and rank the mutations with respect to these. Mutations which occur in all neoplastic cells, i.e. truncal mutations, can be identified by using sequencing-based clonality and allelic frequency estimates. Peptides or, if multiple peptides from a gene are identified, entire genes in the form of so-called tandem minigenes, are then used to stimulate patient T cells in vitro, identifying those mutations that can actually trigger a CD4+ and CD8+ response. The set of mutations thus identified forms the basis of the personalized vaccine.
Having created a manageable library of validated neoepitopes, one still needs to select an optimal design for the synthetic vaccine construct, balancing immunogenicity and safety. The simplest vaccine construct is a pool of 8–11-mer peptides with high efficiency of direct MHC-I loading. However, such short peptides are often used in combination with 20–35 residue long synthetic peptides, which need to be professionally processed, leading to concurrent MHC-I and MHC-II presentation and thus activation of cytotoxic and helper T cells. Anchor residues can be mutated to higher-affinity variants without affecting the TCR-contact residues to increase HLA binding, a process termed heteroclitic optimization. To further increase immunogenicity in the face of the immunosuppressive tumor microenvironment, the peptides can be conjugated to toll-like receptor agonists, STING ligands, or lipidated tails to facilitate uptake by antigen-presenting cells and add context of tissue damage. Peptides can also be delivered in nanoparticles to protect them from degradation and to co-deliver agents that modulate metabolism (e.g., IL-12) or provide checkpoint blockade (e.g., anti-PD-L1 siRNA). This allows precise orchestration of antigen presentation with immunosuppression reversal. Cysteine flanking residues or furin-cleavable linkers can be added to ensure proper intracellular release. Codon-optimized mRNA encoding for a series of concatenated neoepitopes is a highly expressive and transient alternative that avoids peptide synthesis. Every choice along the way is validated in vitro in co-cultures with autologous immune cells to verify that they result in the secretion of multiple cytokines and cytotoxic markers by T cells. The final vaccine construct is molecularly refined and biologically validated, at which point it is ready for clinical testing.
The clinical translation of personalized neoantigen peptides has shifted from early-phase proof-of-concept to multiple oncologic indications. A personalized peptide vaccine cocktail targeting 20 different neoepitopes was safely administered to preclinical models with glioblastoma and resulted in intratumoral infiltration of vaccine-induced T cells, as well as molecular evidence of neoantigen-negative clonal depletion. A DNA-encoded neoantigen vaccine co-expressing IL-12 was shown to induce polyepitopic neoantigen-specific T-cell responses in hepatocellular carcinoma (HCC) and prime the tumor for response to a subsequent checkpoint blockade. A preclinical model with renal collecting-duct carcinoma received a personalized long-peptide vaccine targeting 13 different private mutations and longitudinal biopsies revealed near-ablation of neoantigen-bearing clones within 3 months. Taken together, these brief reports highlight the flexibility, safety, and preclinical impact of personalized peptide-based neoantigen vaccination in multiple tumor types.
Peptide-based immunotherapy represents a novel paradigm in oncology as a modular and streamlined platform. Distilling the heterogeneity of a cancer clone into a single synthetic peptide presents the opportunity to leverage the immense infrastructure of small molecule drug development. In this sense, peptide-based immunotherapy combines the modular simplicity and scalability of small molecule drugs with the precision of tailored therapies. Synthetic peptides represent a well-defined composition and manufacturing process from start to finish – from in silico design, synthesis, in vitro release testing to in vivo administration. All these steps are well established in small molecule drug development and are comparable with GMP-grade quality control, regulatory, and supply chain standards. The active pharmaceutical ingredient (API) itself is a small and easily synthesized chemical compound (synthetic epitope) rather than a virus (vector) or gene (protein) – and thus bypasses the need for GMP-grade gene therapy and cell processing facilities that burden other immunotherapies. Peptide vaccines thus share the logistical advantages of established generic drugs while retaining the specificity and personalization of targeted therapies. Modularly, peptides can be delivered alone or in combination with antibodies, cytokines, or metabolic reprogramming agents – transforming the tumor microenvironment without additional toxicity.
Peptide vaccines are expected to be economically attractive for a number of reasons. Solid-phase peptide synthesis has been a mature technology for decades, uses very little raw material, and will be subject to the accelerated biologics license application route in most jurisdictions. The peptide API can be made in a generic reactor suitable for cGMP synthesis of generic antibiotics, as opposed to cell therapies that require a custom-built clean-room suite for each product. Peptide vaccines are formulated as lyophilized powders and have no cold chain requirements other than the freezer temperature stability that all therapeutic biologics have. The excipients are almost entirely off-patent and the peptide synthesis is also expected to be off-patent once marketed, enabling competing manufacturers to enter the space and drive down the cost. Peptide vaccines do not contain transgenes or infectious organisms and therefore should not require the costly adventitious-agent tests that are a major component of the costs of viral vectors. Because both peptide synthesis and the analytical technology for testing them are mature, it is likely that the products will demonstrate batch-to-batch reproducibility and regulatory agencies should be amenable to waiving full comparability studies after minor process changes. In summary, there should be substantial economies of scale for peptide vaccines, including low regulatory burden, which should allow for very low costs even at the personalized medicine stage.
It's this speed to treatment that's most transformative: from tumor biopsy to first-in-human dosing in as little time as a standard-of-care diagnostic test would take. Hours from next-generation sequencing to ranked lists of candidate peptides from cloud-based neoepitope pipelines, and overnight to milligram-gram scale quantities with automated microwave-assisted peptide synthesizers. Regulatory templates have advanced in lockstep: with the active moiety a well-characterized chemical entity and not a live biologic, toxicology packages can import precedented safety databases for both the adjuvant and the peptide backbone. The reformulation cycle is equally rapid: if longitudinal tumor sampling identifies new mutations, extra epitopes can be added to the same backbone without the need for a complete pre-clinical package to be re-generated. Lyophilization also speeds time to delivery, since just-in-time manufacturing at regional facilities is practical, and not just at centralized facilities. Taken together, the speed of peptide immunotherapy to treatment means the time to therapy matches the underlying biology of aggressive cancers, unlike with cell- or virus-based platforms, which take weeks to months just for amplification and release testing.
Peptide vaccines can be co-administered with most other types of cancer therapy, which means combination approaches are possible and allow vaccination to be more than simply an addition to the available therapies. Peptide-vaccination is synergistic with immunomodulators such as checkpoint inhibitors e.g. anti-PD-1 or anti-CTLA-4, as these remove the suppressive ligands in the tumor environment, leaving activated peptide-specific T cells free to clonally expand and persist as effector cells. Chemotherapy or radiotherapy can also be used as part of a combined approach, their immunosuppressive effects can be offset by co-administration of peptides as they may increase antigen presentation through immunogenic cell death. Peptide boosts administered shortly after a chemotherapy or radiotherapy pulse use the danger signals and release of neoantigens from cell death to their advantage. Oncolytic viruses are another option, they can be modified to express the peptide antigens, turning the tumor cells that infect into antigen-presenting targets to which the vaccine-trained T cells will home. Antibody–drug conjugates can be combined with peptides to ensure co-localization of the ADC and peptide in the tumor bed. Adoptive T-cell transfer protocols could be simplified by vaccinating patients with peptide-pulsed dendritic cells instead of expanding T cells ex-vivo. Peptides have the additional advantage of not having a pharmacokinetic interplay, making possible co-administration with other drugs without requiring complex schedules that are necessary for multi-drug biologics.
Cancer treatment is increasingly moving toward personalization, and peptide-based vaccines are a cornerstone of this evolution. By targeting tumor-specific or neoantigen peptides, these vaccines harness the immune system to recognize and destroy cancer cells. Our peptide vaccine solutions are designed with high purity and validated immunogenicity to deliver strong immune responses. Tailored peptide vaccines improve specificity, reduce toxicity, and provide cost-effective, scalable solutions that complement existing cancer therapies, making them a powerful option in oncology research and treatment development.
Products & Services:
Advantages:
Peptide vaccines combine safety, flexibility, and precision to provide innovative cancer therapies. Work with us to design and deliver personalized peptide vaccines that transform cancer immunotherapy and improve patient outcomes.
1. What are peptide-based cancer vaccines?
They are synthetic peptides designed to trigger anti-tumor immunity.
2. How are neoantigen peptides used?
They target patient-specific tumor mutations.
3. What advantages do peptide vaccines have?
They are safer, cost-effective, and customizable.
References
