Design Of Cancer Vaccines Research Articles

A comprehensive proteogenomic pipeline for neoantigen discovery to advance personalized cancer immunotherapy.

The accurate identification and prioritization of antigenic peptides is crucial for the development of personalized cancer immunotherapies. Publicly available pipelines to predict clinical neoantigens do not allow direct integration of mass spectrometry immunopeptidomics data, which can uncover antigenic peptides derived from various canonical and noncanonical sources. To address this, we present an end-to-end clinical proteogenomic pipeline, called NeoDisc, that combines state-of-the-art publicly available and in-house software for immunopeptidomics, genomics and transcriptomics with in silico tools for the identification, prediction and prioritization of tumor-specific and immunogenic antigens from multiple sources, including neoantigens, viral antigens, high-confidence tumor-specific antigens and tumor-specific noncanonical antigens. We demonstrate the superiority of NeoDisc in accurately prioritizing immunogenic neoantigens over recent prioritization pipelines. We showcase the various features offered by NeoDisc that enable both rule-based and machine-learning approaches for personalized antigen discovery and neoantigen cancer vaccine design. Additionally, we demonstrate how NeoDisc's multiomics integration identifies defects in the cellular antigen presentation machinery, which influence the heterogeneous tumor antigenic landscape.

76. Automating immunogenomic tumor board decision-making for neoantigen cancer vaccine design

76. Automating immunogenomic tumor board decision-making for neoantigen cancer vaccine design

TSpred: a robust prediction framework for TCR-epitope interactions using paired chain TCR sequence data.

Prediction of T-cell receptor (TCR)-epitope interactions is important for many applications in biomedical research, such as cancer immunotherapy and vaccine design. The prediction of TCR-epitope interactions remains challenging especially for novel epitopes, due to the scarcity of available data. We propose TSpred, a new deep learning approach for the pan-specific prediction of TCR binding specificity based on paired chain TCR data. We develop a robust model that generalizes well to unseen epitopes by combining the predictive power of CNN and the attention mechanism. In particular, we design a reciprocal attention mechanism which focuses on extracting the patterns underlying TCR-epitope interactions. Upon a comprehensive evaluation of our model, we find that TSpred achieves state-of-the-art performances in both seen and unseen epitope specificity prediction tasks. Also, compared to other predictors, TSpred is more robust to bias related to peptide imbalance in the dataset. In addition, the reciprocal attention component of our model allows for model interpretability by capturing structurally important binding regions. Results indicate that TSpred is a robust and reliable method for the task of TCR-epitope binding prediction. Source code is available at https://github.com/ha01994/TSpred.

Integrating Multisector Molecular Characterization into Personalized Peptide Vaccine Design for Patients with Newly Diagnosed Glioblastoma.

Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. In this study, we report the findings of four patients enrolled onto the NeoVax clinical trial (NCT0342209). Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells pre- and post-NeoVax for patients 1 to 3 using IFNγ-ELISPOT assay. A statistically significant increase in IFNγ producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from patient 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. Collectively, our findings suggest that NeoVax stimulated the expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in patients with GBM.

Advances in Therapeutic Cancer Vaccines, Their Obstacles, and Prospects Toward Tumor Immunotherapy.

Over the past few decades, cancer immunotherapy has experienced a significant revolution due to the advancements in immune checkpoint inhibitors (ICIs) and adoptive cell therapies (ACTs), along with their regulatory approvals. In recent times, there has been hope in the effectiveness of cancer vaccines for therapy as they have been able to stimulate de novo T-cell reactions against tumor antigens. These tumor antigens include both tumor-associated antigen (TAA) and tumor-specific antigen (TSA). Nevertheless, the constant quest to fully achieve these abilities persists. Therefore, this review offers a broad perspective on the existing status of cancer immunizations. Cancer vaccine design has been revolutionized due to the advancements made in antigen selection, the development of antigen delivery systems, and a deeper understanding of the strategic intricacies involved in effective antigen presentation. In addition, this review addresses the present condition of clinical tests and deliberates on their approaches, with a particular emphasis on the immunogenicity specific to tumors and the evaluation of effectiveness against tumors. Nevertheless, the ongoing clinical endeavors to create cancer vaccines have failed to produce remarkable clinical results as a result of substantial obstacles, such as the suppression of the tumor immune microenvironment, the identification of suitable candidates, the assessment of immune responses, and the acceleration of vaccine production. Hence, there are possibilities for the industry to overcome challenges and enhance patient results in the coming years. This can be achieved by recognizing the intricate nature of clinical issues and continuously working toward surpassing existing limitations.

Heat Shock Proteins, a Double-Edged Sword: Significance in Cancer Progression, Chemotherapy Resistance and Novel Therapeutic Perspectives.

Heat shock proteins (Hsps) are involved in one of the adaptive mechanisms protecting cells against environmental and metabolic stress. Moreover, the large role of these proteins in the carcinogenesis process, as well as in chemoresistance, was noticed. This review aims to draw attention to the possibilities of using Hsps in developing new cancer therapy methods, as well as to indicate directions for future research on this topic. In order to discuss this matter, a thorough review of the latest scientific literature was carried out, taking into account the importance of selected proteins from the Hsp family, including Hsp27, Hsp40, Hsp60, Hsp70, Hsp90 and Hsp110. One of the more characteristic features of all Hsps is that they play a multifaceted role in cancer progression, which makes them an obvious target for modern anticancer therapy. Some researchers emphasize the importance of directly inhibiting the action of these proteins. In turn, others point to their possible use in the design of cancer vaccines, which would work by inducing an immune response in various types of cancer. Due to these possibilities, it is believed that the use of Hsps may contribute to the progress of oncoimmunology, and thus help in the development of modern anticancer therapies, which would be characterized by higher effectiveness and lower toxicity to the patients.

Abstract SY41-02: Experimental methods for high throughput discovery and validation of tumor antigens

Abstract The discovery and validation of tumor associated T-cell antigens, which can include neoantigens, viral antigens, cancer testis antigens, and others, is fundamental to the design of both cancer vaccines and engineered cell cancer immunotherapies. However, identifying tumor specific antigens that are highly presented within tumors, and identifying and validating T cell receptors (TCRs) that are specific to those antigens, remains a non-trivial exercise. Even identifying and validating a single antigen-specific T cell clonotype for advancement into a clinic trial remains a daunting task. In this talk, I will discuss a number of new experimental and computational tools that are designed to accelerate this process. The experimental toolsets include reagents and strategies that allow for the capture and analysis of T cells specific to hundreds to thousands of tumor-associated Class I and Class II antigens simultaneously, with as many as 100 patient bloods analyzed in a single experiment. Single cell analysis of the resulting data yields a deep characterization of the captured T cells, including T cell receptor α/β genes, antigen-MHC specificity, T cell phenotype, and donor identification. This type of analysis, in turn, provides large data bases that can fuel new computational strategies that can be harnessed (at a still early stage) to predict which TCRα/β genes associate with which putative antigen-MHCs, or to extract the biochemical and biophysical characteristics of TCR-antigen pairings that influence T cell phenotype. Thus, this presentation will span both new experimental and new computational toolsets. Citation Format: James R. Heath. Experimental methods for high throughput discovery and validation of tumor antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY41-02.

Antigen-Clustered Nanovaccine Achieves Long-Term Tumor Remission by Promoting B/CD 4 T Cell Crosstalk.

Current cancer vaccines using T cell epitopes activate antitumor T cell immunity through dendritic cell/macrophage-mediated antigen presentation, but they lack the ability to promote B/CD4 T cell crosstalk, limiting their anticancer efficacy. We developed antigen-clustered nanovaccine (ACNVax) to achieve long-term tumor remission by promoting B/CD4 T cell crosstalk. The topographic features of ACNVax were achieved using an iron nanoparticle core attached with an optimal number of gold nanoparticles, where the clusters of HER2 B/CD4 T cell epitopes were conjugated on the gold surface with an optimal intercluster distance of 5-10 nm. ACNVax effectively trafficked to lymph nodes and cross-linked with BCR, which are essential for stimulating B cell antigen presentation-mediated B/CD4 T cell crosstalk in vitro and in vivo. ACNVax, combined with anti-PD-1, achieved long-term tumor remission (>200 days) with 80% complete response in mice with HER2+ breast cancer. ACNVax not only remodeled the tumor immune microenvironment but also induced a long-term immune memory, as evidenced by complete rejection of tumor rechallenge and a high level of antigen-specific memory B, CD4, and CD8 cells in mice (>200 days). This study provides a cancer vaccine design strategy, using B/CD4 T cell epitopes in an antigen clustered topography, to achieve long-term durable anticancer efficacy through promoting B/CD4 T cell crosstalk.

Activated B-Cells enhance epitope spreading to support successful cancer immunotherapy.

Immune checkpoint therapies (ICT) have transformed the treatment of cancer over the past decade. However, many patients do not respond or suffer relapses. Successful immunotherapy requires epitope spreading, but the slow or inefficient induction of functional antitumoral immunity delays the benefit to patients or causes resistances. Therefore, understanding the key mechanisms that support epitope spreading is essential to improve immunotherapy. In this review, we highlight the major role played by B-cells in breaking immune tolerance by epitope spreading. Activated B-cells are key Antigen-Presenting Cells (APC) that diversify the T-cell response against self-antigens, such as ribonucleoproteins, in autoimmunity but also during successful cancer immunotherapy. This has important implications for the design of future cancer vaccines.

MHCII-peptide presentation: an assessment of the state-of-the-art prediction methods.

Major histocompatibility complex Class II (MHCII) proteins initiate and regulate immune responses by presentation of antigenic peptides to CD4+ T-cells and self-restriction. The interactions between MHCII and peptides determine the specificity of the immune response and are crucial in immunotherapy and cancer vaccine design. With the ever-increasing amount of MHCII-peptide binding data available, many computational approaches have been developed for MHCII-peptide interaction prediction over the last decade. There is thus an urgent need to provide an up-to-date overview and assessment of these newly developed computational methods. To benchmark the prediction performance of these methods, we constructed an independent dataset containing binding and non-binding peptides to 20 human MHCII protein allotypes from the Immune Epitope Database, covering DP, DR and DQ alleles. After collecting 11 known predictors up to January 2022, we evaluated those available through a webserver or standalone packages on this independent dataset. The benchmarking results show that MixMHC2pred and NetMHCIIpan-4.1 achieve the best performance among all predictors. In general, newly developed methods perform better than older ones due to the rapid expansion of data on which they are trained and the development of deep learning algorithms. Our manuscript not only draws a full picture of the state-of-art of MHCII-peptide binding prediction, but also guides researchers in the choice among the different predictors. More importantly, it will inspire biomedical researchers in both academia and industry for the future developments in this field.

Cancer vaccines: from an immunology perspective.

The concept of a therapeutic cancer vaccine to activate anti-tumour immunity pre-dates innovations in checkpoint blockade immunotherapies. However, vaccination strategies have yet to show the hoped-for successes in patients, and unanswered questions regarding the underlying immunological mechanisms behind cancer vaccines have hampered translation to clinical practice. Recent advances in our understanding of the potential of tumour mutational burden and neo-antigen-reactive T cells for response to immunotherapy have re-ignited enthusiasm for cancer vaccination strategies, coupled with the development of novel mRNA-based vaccines following successes in prevention of COVID-19. Here we summarise current developments in cancer vaccines and discuss how advances in our comprehension of the cellular interplay in immunotherapy-responsive tumours may inform better design of therapeutic cancer vaccines, with a focus on the role of dendritic cells as the orchestrators of anti-tumour immunity. The increasing number of clinical trials and research being funnelled into cancer vaccines has demonstrated the 'proof-of-principle', supporting the hypothesis that therapeutic vaccines have potential as an immuno-oncology agent. For efficacious and safe cancer vaccines to be developed, better understanding of the underpinning immunological mechanisms is paramount.

Hybrid LNP Prime Dendritic Cells for Nucleotide Delivery.

The efficient activation of professional antigen-presenting cells-such as dendritic cells (DC)-in tumors and lymph nodes is critical for the design of next-generation cancer vaccines and may be able to provide anti-tumor effects by itself through immune stimulation. The challenge is to stimulate these cells without causing excessive toxicity. It is hypothesized that a multi-pronged combinatorial approach to DC stimulation would allow dose reductions of innate immune receptor-stimulating TLR3 agonists while enhancing drug efficacy. Here, a hybrid lipid nanoparticle (LNP) platform is developed and tested for double-stranded RNA (polyinosinic:polycytidylic acid for TLR3 agonism) and immune modulator (L-CANDI) delivery. This study shows that the ≈120nm hybrid nanoparticles-in-nanoparticles effectively eradicate tumors by themselves and generate long-lasting, durable anti-tumor immunity in mouse models.

Carrier-Free Nanovaccine: An Innovative Strategy for Ultrahigh Melanoma Neoantigen Loading.

In personalized cancer immunotherapy, developing an effective neoantigen nanovaccine with high immunogenicity is a significant challenge. Traditional nanovaccine delivery systems often require nanocarriers, which can hinder the delivery of the neoantigen and cause significant toxicity. In this study, we present an innovative strategy of carrier-free nanovaccine achieved through direct self-assembly of 2'-fluorinated CpG (2'F-CpG) with melanoma neoantigen peptide (Obsl1). Molecular dynamics simulations demonstrated that the introduction of a fluorine atom into CpG increases the noncovalent interaction between 2'F-CpG and Obsl1, which enhanced the loading of Obsl1 on 2'F-CpG, resulting in the spontaneous formation of a hybrid 2'F-CpG/Obsl1 nanovaccine. This nanovaccine without extra nanocarriers showed ultrahigh Obsl1 loading up to 83.19 wt %, increasing the neoantigen peptide uptake by antigen-presenting cells (APCs). In C57BL/6 mice models, we demonstrated the long-term preventive and therapeutic effects of the prepared 2'F-CpG/Obsl1 nanovaccine against B16F10 melanoma. Immunocellular analysis revealed that the nanovaccine activated innate and adaptive immune responses to cancer cells. Hence, this study established a simple, safe, and effective preparation strategy for a carrier-free neoantigen nanovaccine, which could be adapted for the future design of personalized cancer vaccines in clinical settings.

Cancer testis antigen subfamilies: Attractive targets for therapeutic vaccine (Review).

Cancer‑testis antigen (CTA) is a well‑accepted optimal target library for cancer diagnosis and treatment. Most CTAs are located on the X chromosome and aggregate into large gene families, such as the melanoma antigen, synovial sarcoma X and G antigen families. Members of the CTA subfamily are usually co‑expressed in tumor tissues and share similar structural characteristics and biological functions. As cancer vaccines are recommended to induce specific antitumor responses, CTAs, particularly CTA subfamilies, are widely used in the design of cancer vaccines. To date, DNA, mRNA and peptide vaccines have been commonly used to generate tumor‑specific CTAs invivo and induce anticancer effects. Despite promising results in preclinical studies, the antitumor efficacy of CTA‑based vaccines is limited in clinical trials, which may be partially attributed to weak immunogenicity, low efficacy of antigen delivery and presentation processes, as well as a suppressive immune microenvironment. Recently, the development of nanomaterials has enhanced the cancer vaccination cascade, improved the antitumor performance and reduced off‑target effects. The present study provided an in‑depth review of the structural characteristics and biofunctions of the CTA subfamilies, summarised the design and utilisation of CTA‑based vaccine platforms and provided recommendations for developing nanomaterial‑derived CTA‑targeted vaccines.

Advances in Cancer Nanovaccines: Harnessing Nanotechnology for Broadening Cancer Immune Response.

Many advances have been made recently in the field of cancer immunotherapy, particularly with the development of treatments such as immune checkpoint inhibitors and adoptive cellular immunotherapy. The efficacy of immunotherapy is limited, however, owing to high levels of tumor heterogeneity and the immunosuppressive environments of advanced malignant tumors. Therefore, therapeutic anticancer vaccines have gradually become powerful tools for inducing valid antitumor immune responses and regulating the immune microenvironment. Tumor vaccines loaded in nanocarriers have become an indispensable delivery platform for tumor treatment because of their enhanced stability, targeting capability, and high level of safety. Through a unique design, cancer nanovaccines activate innate immunity and tumor-specific immunity simultaneously. For example, the design of cancer vaccines can incorporate strategies such as enhancing the stability and targeting of tumor antigens, combining effective adjuvants, cytokines, and immune microenvironment regulators, and promoting the maturation and cross-presentation of antigen-presenting cells (APCs). In this review, we discuss the design and preparation of nanovaccines for remodeling tumor antigen immunogenicity and regulating the immunosuppressive microenvironment.

Mannan-decorated STING-activating vaccine carrier for spatial coordinative stimulating antigen-specific immune responses

In recent years, the use of nanotechnologies to improve immunotherapy efficiency has attracted increasing interest in preventive and therapeutic cancer vaccine design. However, current nanocarriers are restricted by difficulties in the systematic spatial coordinative transport of antigens, which greatly hampers the immune response efficacy of nanovaccines. Herein, we designed a mannan-decorated stimulator of the interferon genes (STING)-activating vaccine carrier for spatial coordinative stimulation of antigen-specific immune responses and elicitation of robust antitumor immunity. Mannan-decoration as the shell could significantly enhance the lymph node draining ability of the nanovaccines, especially in CD8+ dendritic cells (DCs). Azole molecule end-capped polylactic acid-polyethylenimine (PLA-PEI-4BImi) with innate stimulating activity was applied as the inner core for coordinating antigen-presenting cell activation and antigen cross-presentation. In the in vivo therapy study, single usage of this nanovaccine could achieve a 93% tumor suppression rate in the B16-OVA tumor model, which is superior to the commercialized aluminum adjuvant. This study demonstrates that a rational design of vaccine carriers for solving spatial transmission issues could greatly improve cancer vaccine efficiencies.

CaCO3 powder-mediated biomineralization of antigen nanosponges synergize with PD-1 blockade to potentiate anti-tumor immunity

Antigen self-assembly nanovaccines advance the minimalist design of therapeutic cancer vaccines, but the issue of inefficient cross-presentation has not yet been fully addressed. Herein, we report a unique approach by combining the concepts of “antigen multi-copy display” and “calcium carbonate (CaCO3) biomineralization” to increase cross-presentation. Based on this strategy, we successfully construct sub-100 nm biomineralized antigen nanosponges (BANSs) with high CaCO3 loading (38.13 wt%) and antigen density (61.87%). BANSs can be effectively uptaken by immature antigen-presenting cells (APCs) in the lymph node upon subcutaneous injection. Achieving efficient spatiotemporal coordination of antigen cross-presentation and immune effects, BANSs induce the production of CD4+ T helper cells and cytotoxic T lymphocytes, resulting in effective tumor growth inhibition. BANSs combined with anti-PD-1 antibodies synergistically enhance anti-tumor immunity and reverse the tumor immunosuppressive microenvironment. Overall, this CaCO3 powder-mediated biomineralization of antigen nanosponges offer a robust and safe strategy for cancer immunotherapy.

Nanovaccines for cancer immunotherapy: Current knowledge and future perspectives

Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years. Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells (APCs) to stimulate a strong immune response to against tumors, representing a potentially therapeutic and prophylactic effect with the long-term anti-cancer benefits. Nevertheless, the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection, immunogenicity, lymph nodes (LNs) targeting ability, lysosomal escape ability, immune evasion, etc. Nanotechnology, aiming to overcome these barriers, has been utilized in cancer vaccine development for decades. Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy. In this review, we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design. In addition, the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.

In Silico Pipeline to Identify Tumor-Specific Antigens for Cancer Immunotherapy Using Exome Sequencing Data.

The online version contains supplementary material available at 10.1007/s43657-022-00084-9.

Advances in Tumor Antigen‐Based Anticancer Immunotherapy: Recent Progress, Prevailing Challenges, and Future Perspective

AbstractElimination of tumors by regulating the immune system is the primary research focus in the rapidly developing field of immune‐oncology. Current immunotherapeutic strategies mainly include immune checkpoint blockade therapy, adoptive immune cell therapy, and cancer vaccines. Among them, tumor antigen‐based cancer vaccines can potentially elicit specific and potent anti‐tumor immune responses with less toxicity and side effects, which are recognized as promising treatments in immunotherapy. The selection of tumor antigens is the primary determinant of cancer vaccine design, whereas systematic reviews based on them are scarce. In the present review, currently known tumor antigens and recent developments in cancer vaccines based on tumor antigens, including traditional antigen vaccines, neoantigen vaccines, shared antigen vaccines, and oral antigen vaccines, in hopes of providing fundamental basis for further development of novel cancer vaccine‐based therapies, are summarized.