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Artificial intelligence for translational personalized neoantigen cancer vaccine development.

Personalized neoantigen cancer vaccine is a promising strategy for precision immunotherapy by targeting patient-specific and mutation-derived tumor antigens. Early clinical studies have demonstrated the feasibility, safety, and immunogenicity of these vaccines across multiple solid tumors, with encouraging outcomes particularly when combined with immune checkpoint blockade. However, broader clinical translation remains limited by sequential bottlenecks across the vaccine development pipeline, including false-positive neoantigen selection,  imperfect modeling of antigen processing and HLA presentation, limited prediction of T-cell receptor recognition, and challenges in formulation, delivery, and manufacturing. Artificial intelligence and advanced computational workflows are increasingly integrated into this pipeline to improve candidate prioritization and support more reproducible decision-making. In this review, we summarize clinical progress and key translational barriers in personalized neoantigen vaccination, and discuss how AI-enabled approaches may contribute across four major stages: multi-omics integration for neoantigen discovery, processing-aware HLA presentation prediction, structure-aware and TCR-informed immunogenicity modeling, and data-driven formulation optimization, particularly for lipid nanoparticle-based delivery systems. These approaches are able to help narrow biological and chemical search spaces, improve prioritization, and provide mechanistic insights into antigen presentation and immune recognition rather than replacing experimental validation. This articlefurther addresses future implementation challenges, including dataset diversity, model interpretability, prospective benchmarking, manufacturing traceability, and evolving regulatory frameworks for individualized mRNA cancer immunotherapies. Integrating computational innovation with rigorous immunological validation, scalable manufacturing, and regulatory oversight will be essential for advancing personalized neoantigen vaccines toward broader clinical implementation.

Cancer Vaccines

Synthetic long peptide and DNA personalized cancer vaccines induce robust neoantigen-specific T cell responses in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is unresponsive to standard immunotherapies despite harboring cancer neoantigens capable of eliciting T cell responses. We completed two phase 1 clinical trials (NCT03956056 and NCT03122106) evaluating safety and immunogenicity of synthetic long peptide (SLP) and DNA personalized cancer vaccines (PCVs). PCVs were administered after resection and adjuvant chemotherapy. Tumor/normal whole-exome sequencing, RNA sequencing, and pVACtools were used to identify and prioritize candidate PCV neoantigens. PCVs were well tolerated without any grade ≥3 adverse events. Neoantigen-specific responses were demonstrated by interferon-γ enzyme-linked immunospot and intracellular cytokine staining. Expanded T cell receptor clonotypes were sequenced and transduced into autologous peripheral blood mononuclear cells to confirm neoantigen specificity. When compared with a contemporaneous institutional propensity-matched cohort, PCV patients demonstrated a trend toward prolonged median overall survival (4.4 versus 3.5 years, log-rank P = 0.23). Overall, PDAC PCVs are safe and feasible and elicit polyclonal T cell responses, linking prioritized cancer neoantigens to functional antitumor immunity.

Humans

Epitope- and antigen-specific cancer vaccines.

Anti-idiotypic antibodies (Ab2) that functionally mimic epitopes associated with human cancer cells are the most specific cancer vaccines currently available. Ab2 can induce specific humoral anti-tumor immunity in cancer patients. However, the potential of Ab2 for inducing cellular immunity in cancer patients still requires demonstration. Clonotypic antibodies directed against the combining site for tumor Ag on human T-cell clones may provide highly effective reagents for inducing protective T-cell immunity against human cancer. A new generation of cancer vaccines, molecularly cloned tumor-associated antigens (Ag), has recently been developed. Recombinant Ag have been successfully expressed in vectors allowing large scale production of Ag for immunization of cancer patients. Recombinant tumor Ag was shown to induce specific and protective immunity in experimental animals. In contrast to Ab2, which may mimic a single cancer-associated epitope, recombinant Ag express multiple epitopes that are potentially immunogenic. Ag vaccines, therefore, may be more effective in arresting tumor growth than single epitope (Ab2) vaccines because tumor destruction by antibodies is dependent on antibody density on tumor cell surfaces. In light of the important roles that both B and T cells play in the control of tumor growth, the demonstration of induction of specific B and T cell-immunity by recombinant tumor Ag and Ab2 in experimental animals is encouraging. Ultimately, the immunomodulatory role of both types of vaccines has to be compared in cancer patients who are immunologically tolerant to many Ag/epitopes expressed by their growing tumors. The development of both Ab2 and recombinant Ag for single antigenic systems provides the first step towards this goal.

Antibodies, Anti-Idiotypic

Immunopeptidomics-guided cancer vaccine design: Advances, challenges, and emerging opportunities.

Selecting clinically relevant tumor antigens remains a major challenge in the development of therapeutic cancer vaccines. Although computational approaches have considerably improved neoantigen prediction, many candidate epitopes identified in silico are not ultimately presented on the tumor cell surface. The emergence of immunopeptidomics has provided direct access to naturally processed HLA-associated peptides and has offered new opportunities for antigen discovery. Increasing evidence has shown that information derived from the immunopeptidome becomes considerably more informative when interpreted alongside genomic, transcriptomic, and proteomic data. This integrative view has broadened the spectrum of targetable antigens and has also revealed important limitations related to peptide abundance, HLA diversity, tumor heterogeneity, and the imperfect relationship between antigen presentation and immunogenicity. These issues have renewed interest in multi-antigen vaccine strategies designed to better reflect the complexity of tumor antigen landscapes. Advances in bioinformatics and artificial intelligence are facilitating the interpretation of increasingly complex datasets and are beginning to support more systematic approaches to antigen prioritization. In this review, we discuss how immunopeptidomics is contributing to next-generation cancer vaccine development, summarize the major translational challenges, and highlight emerging concepts that may improve the clinical applicability of immunopeptidomics-guided immunotherapy.

Cancer immunotherapy

Beyond Canonical Neoantigens: Emerging Technologies for Identification of Noncanonical Antigens and Implications for Personalized Cancer Vaccines.

Over the past decade, advances in sequencing technologies and computational pipelines enabled the development of personalized cancer vaccines (PCVs). Current PCV strategies primarily target cancer neoantigens generated by non-synonymous DNA mutations, which can result in altered amino acid sequences capable of eliciting tumor-specific immune responses. More recently, a distinct class of tumor-specific antigens (TSA), termed noncanonical or cryptic antigens, has emerged as an additional source of immunogenic targets. Unlike canonical neoantigens, noncanonical antigens typically cannot be identified by tumor/normal whole-exome sequencing, as they do not arise from classical DNA mutations. Instead, they are often associated with less well recognized and/or aberrant processes in the pathways from DNA to human leukocyte antigen (HLA)-presented peptides. Examples include transposable elements, circular RNA, translation of alternative open reading frames and/or long non-coding RNA, among others. Emerging evidence suggests that noncanonical antigens represent a substantial portion of the tumor-specific immunopeptidome and, similar to canonical neoantigens, are absent during thymic selection and can evade central tolerance and elicit T cell responses. Technological advances have increasingly facilitated the identification of noncanonical antigens. Long-read RNA sequencing reveals noncanonical transcripts by improving transcriptome assembly, while ribosome profiling provides genome-wide maps of actively translated regions, facilitating the discovery of peptides from aberrant translation events. Specialized molecular approaches enable enrichment and sequencing of circular RNAs, and immunopeptidomics using mass spectrometry allows for direct characterization of HLA-presented peptides. Together, these technological advances have led to an increasing interest in prioritizing and targeting noncanonical antigens in the next generation of PCVs. This review provides an overview of the diverse origins of TSAs beyond classical neoantigens and discusses emerging approaches that may enable the integration of these antigens in future clinical trials.

circular RNA

Cellular and humoral immune responses against cancer: implications for cancer vaccines.

The key issue in tumor immunology is to identify antigens as target structures for a cancer-selective immunological attack in the tumor-bearing host, resulting in tumor rejection. There is a growing detailed understanding of structural and regulatory gene alterations giving rise to candidate rejection antigens and peptides in tumor cells. As well as reviewing the development of new adjuvant and recombinant vector systems, new approaches are suggested for the construction of cancer vaccines.

Animals

Plant-derived recombinant macromolecular PAP-IgG Fc as a novel prostate cancer vaccine candidate eliciting robust immune responses.

Prostatic acid phosphatase (PAP) is a specific protein that is highly expressed in prostate cancer. In this study, we constructed two recombinant PAP fusion genes: PAP fused to the immunoglobulin G (IgG) Fc fragment (designated PAP-Fc) and PAP-Fc fused to the endoplasmic reticulum retention sequence KDEL (designated PAP-FcK). Transgenic Nicotiana tabacum plants expressing these recombinant macromolecular proteins (MPs) were generated using Agrobacterium-mediated transformation, and the presence of both genes was confirmed through genomic PCR. Western blot analysis validated the expression of PAP-Fc and PAP-FcK MPs, which were successfully purified via protein A affinity chromatography. Size-exclusion high-performance liquid chromatography revealed dimeric peaks for PAP-Fc (PAP-FcP) and PAP-FcK (PAP-FcKP). Bio-transmission electron microscopy demonstrated 'Y'-shaped protein particles resembling antibody structures. Moreover, PAP-FcP and PAP-FcKP exhibited a high association rate with human FcγR and FcRn. Vaccination of mice with both PAP-FcP and PAP-FcKP resulted in increased total IgG against PAP and enhanced activation of CD4+ T cells, comparable to mice immunized with PAP, which served as a positive control. These findings indicate that both plant-derived MPs can effectively induce adaptive immunity, positioning them as promising candidates for prostate cancer vaccines. Overall, plants expressing PAP-Fc and PAP-FcK represent a viable production system for antigenic macromolecule-based prostate cancer vaccines.

Male

Immunity and metastasis: in situ activation of protective T cells by virus modified cancer vaccines.

Data from animal models and clinical observations from immunotherapy trials suggest that tumour reactive host T cells can have an important role in the control of metastasis and tumour rejection. If tumour cells express tumour associated antigens recognizable by T cells, their antigenicity/immunogenicity is usually weak, and accessory molecules are required to stabilize the T cell/tumour cell interaction and to deliver the antigen/T cell receptor (TCR) mediated signal (signal 1) together with costimulatory signals (signal 2). The sum of these intracellular signals received by the corresponding T cells with the fitting TCR may determine the intensity of the anti-tumour response. A deficiency of anti-tumour T cell responsiveness in cancer patients could thus be due to a lack of signal 1 and/or signal 2 or to inappropriate timing between the two signals. A further point to consider is the distinction between primary and secondary T cell responses: between priming of virgin T cells and activation of primed memory T cells. Our experience with a metastasizing animal tumour suggests that the microenvironmental requirements for these two steps differ. This means that the site of a primary (or secondary) tumour may be good for one type of response (eg priming) but not for the other (eg memory response). One purpose of active immunotherapy could therefore consist of exposing the cancer patient's immune system to its own tumour cells in the context of a new microenvironment that may be well suited for activating memory type responses. On the basis of these considerations, we discuss the possibilities of immunological intervention and propose the use of a two-component cancer vaccine for active immunization and two signal stimulation of endogenous memory T cells in tumour bearing animals or cancer patients. As a specific component, we favour the use of intact, viable, radiation inactivated autologous tumour cells, which should represent the closest match to the patient's own cancer. If this is not possible, cells from allogeneic corresponding tumours or tumour cell lines could be used. On a longer time scale of treatment, one may consider an induction therapy with autologous vaccine followed by maintenance therapy (when autologous material has run out) with allogeneic material. As a second non-specific component, we favour and have good experience with a virus, NDV, which can easily attach to the cells of the vaccine and facilitate the delivery of costimulatory signals to tumour reactive T cells following postoperative vaccination of tumour bearing hosts.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals

A Programmable Nanovaccine Platform Based on M13 Bacteriophage for Personalized Cancer Vaccine and Therapy.

Nanovaccines co-assemble antigens and adjuvants to elicit robust immune responses but often require complex synthesis and post-modification procedures. Here, a programmable nanovaccine platform based on the M13 bacteriophage is developed for the scalable production of vaccines and single-step modular engineering of adjuvanticity, length, and antigen density. By reprogramming the sequence and size of the noncoding phage genome, the Toll-like receptor 9 activation and the length of the phage are precisely controlled. With a novel molecular engineering approach, the antigen density is tuned from 13.6% to 70.3%. A systematic modulation reveals an optimal adjuvanticity at a constant antigen density for maximum anti-tumor CD8+ T cell response, and vice versa, using the model antigen SIINFEKL. The M13 phage-based nanovaccine induces durable memory immunity lasting over a year. In addition, a 24-fold increase in neoantigen-specific CD8+ T cell frequency is achieved when increasing both the adjuvanticity and antigen density. Furthermore, when combined with anti-PD-1 therapy, the M13 phage-based personalized vaccine eradicates established MC-38 tumors in 75% of treated animals and they develop 100% resistance against tumor invasion when challenged 5 months after treatment. These findings establish M13 phage as a powerful and versatile nanovaccine platform with transformative potential for personalized cancer immunotherapy.

Cancer Vaccines

[BCG vaccination, cancer and infectious mononucleosis. A retrospective study of hospitalized patients].

A retrospective study (1966--1976) of patients hospitalized for cancer was carried out to determine a possible relationship with BCG vaccination, with a control group matched for age and sex and a similar study concerning infectious mononucleosis. Among 105 patients with cancer, 54 (51.42%) had been previously vaccinated with BCG, 56 (53.33%) in the control group, and 22 (33.84%) among the 65 patients with infectious mononucleosis (p less than 0.05, x2). The mean age on admission for cancer or infectious mononucleosis among vaccinees is significantly older than among non-vaccinees, suggesting a transient protection afforded by vaccination. These results need to be confirmed by a prospective study with Epstein-Barr virus serology.

Age Factors

Anti-idiotype cancer vaccines: pre-clinical and clinical studies.

We have previously shown that anti-idiotypic antibodies (Ab2) that functionally mimic the epitope defined by anti-colorectal carcinoma (CRC) monoclonal antibody (Ab1) CO17-1A induce in cancer patients highly specific anti-anti-idiotypic antibodies (Ab3) which are Ab1-like in their binding specificity to tumor cells and antigen. Ab1 GA733, originally produced against gastric carcinoma, binds to the same antigen as Ab1 CO17-1A, but to a different epitope. Ab2 against Ab1 GA733 produced in goats have been previously shown in experimental animals to functionally mimic the epitope defined by the Ab1. For the purposes of studying immune responses, this Ab2 preparation was administered to 12 patients who had previously been diagnosed with CRC but whose tumors were excised prior to Ab2 therapy. Patients were injected subcutaneously with escalating doses (0.5-4 mg) of Ab2 precipitated to alum. Ten of the 12 patients produced antibodies to the administered Ab2. In six patients a fraction of these antibodies bound specifically to the Ab2 and not to normal goat IgG. These anti-anti-idiotypic antibodies (Ab3) shared idiotopes with the Ab1 and bound to antigen-positive, but not antigen-negative, cultured tumor cells. The Ab3 specifically inhibited binding of the Ab1 to tumor cells and therefore may bind to the same epitope as Ab1. Our studies demonstrate that Ab2 are highly specific modulators of cancer patients immune responses to their tumors.

Antibodies, Anti-Idiotypic

Construction of cancer vaccines with carbohydrate and protein (peptide) tumor antigens.

Tumor vaccinology is as old as immunological thought and as young as our rapidly evolving understanding of antigen processing and presentation. The recent availability of carbohydrate and peptide tumor antigens suitable for vaccine construction, conjugate and recombinant vector technologies capable of augmenting helper and cytotoxic T cell activity and potent new immunological adjuvants have combined to produce considerable optimism for the future of tumor vaccines.

Antigens, Neoplasm