Development Of Cancer Vaccines Research Articles

Breaking barriers: Smart vaccine platforms for cancer immunomodulation.

Despite significant advancements in cancer treatment, current therapies often fail to completely eradicate malignant cells. This shortfall underscores the urgent need to explore alternative approaches such as cancer vaccines. Leveraging the immune system's natural ability to target and kill cancer cells holds great therapeutic potential. However, the development of cancer vaccines is hindered by several challenges, including low stability, inadequate immune response activation, and the immunosuppressive tumor microenvironment, which limit their efficacy. Recent progress in various fields, such as click chemistry, nanotechnology, exosome engineering, and neoantigen design, offer innovative solutions to these challenges. These achievements have led to the emergence of smart vaccine platforms (SVPs), which integrate protective carriers for messenger ribonucleic acid (mRNA) with functionalization strategies to optimize targeted delivery. Click chemistry further enhances SVP performance by improving the encapsulation of mRNA antigens and facilitating their precise delivery to target cells. This review highlights the latest developments in SVP technologies for cancer therapy, exploring both their opportunities and challenges in advancing these transformative approaches.

An in vitro nanocarrier-based B cell antigen loading system; tumor growth suppression via transfusion of the antigen-loaded B cells in vivo.

B cell-based vaccines are expected to provide an alternative to DC-based vaccines. However, the efficacy of antigen uptake by B cells in vitro is relatively low, and efficient antigen-loading methods must be established before B cell-based vaccines are viable in clinical settings. We recently developed an in vitro system that efficiently loads antigens into isolated splenic B cells via liposomes decorated with hydroxyl PEG (HO-PEG-Lips). Therefore, the purpose of this study was to expand this system in order to achieve another approach to in vivo tumor growth suppression. By using HO-PEG-Lips as a carrier for model antigen OVA along with an adjuvant, α-galactosylceramide (GC), the amount of antigen loading to the B cells in vitro was increased compared with that of both free OVA and free GC. Transfusion of B cells treated with HO-PEG-Lips that encapsulated OVA and GC suppressed the growth of OVA-expressing murine thymoma (E.G7-OVA) tumors in vivo through strong induction of OVA-specific T cells. Under fluorescence microscopic observation, migration of the transfused B cells in the spleens of recipient mice were confirmed. Our results indicate that our novel antigen-loading system could become a promising approach to facilitate the development of cell-based therapeutic cancer vaccines utilizing B cells as alternative APCs.

Preclinical development of the lipid nanoparticle–based mRNA vaccine with multiple natural T cell epitopes for pancreatic cancer.

752 Background: Immunotherapy has recently emerged as a promising avenue in cancer treatment; however, its effectiveness on pancreatic ductal adenocarcinoma (PDAC) is hindered by the lack of effector T cells in the tumor microenvironment. One of the strategies to overcome the resistance of PDAC to immunotherapy involves identifying immunogenic tumor-associated and specific antigens for the development of personalized cancer vaccines. The mRNA platform has become an attractive platform for antigen presentation. The delivery of mRNA cancer vaccines via lipid nanoparticles (LNPs) enables intracellular delivery and controlled release of the payload, offering improved vaccine efficacy. However, mRNA vaccines presenting human T cell epitopes often lack a preclinical model for antitumor immune efficacy testing. Methods: A syngeneic mouse model of PDACs was established by implanting KPC tumor cells into the livers by hemispleen surgery. mRNA vaccine expressing five 25-mer peptide regions were synthesized. Two mouse CD8+ T cell epitopes were predicted. Their MHC binding was tested by the T2 binding assay. CD8+ T cells specific for these two epitopes were examined by ELISpot assays and were quantified by ImmunoSpot ELISpot Reader to identify changes in IFN-g secretion. Results: Using mass spectrometry analysis, we successfully identified natural HLA class I and class II-binding epitopes in the neoplastic tissues of human PDACs. For the design of mRNA vaccine, we chose five 25-mer peptide regions that each contains both class I and class II epitopes punctuated by AAY and GPGPG linkers and followed by an MITD sequence, which all aim to improve the efficiency of antigen presentation to dendritic cells. Using NetMHC, we predicted H2Kb or H2Db-binding epitopes LYPFPLAL and SMVQMTFL, within these five human peptide regions. The T2 binding assay showed a lack of evident binding of both peptides to the T2-Kb or T2-Db cells. However, the ELISpot assay showed that LYPFPLAL, but not SMVQMTFL, can induce the IFN-g expression from CD8+ T cells derived from splenocytes of the KPC tumor mice vaccinated by a peptide vaccine containing both peptides. Therefore, this result confirmed that LYPFPLAL is a mouse CD8+ T cell epitope and can be used to monitor antigen-specific CD8+ T cell response in response to the mRNA vaccine treatment in the syngeneic mouse model of PDACs. Conclusions: Antitumor efficacy of our above-designed mRNA vaccine can be tested in the syngeneic mouse hemispleen model of KPC tumors. Mouse LYPFPLAL epitope-specific CD8+ T cell response can serve as a surrogate marker for the antitumor efficacy of this mRNA vaccine in mouse models for PDAC.

A new weapon: the application of tumor vaccines based on extracellular exosomal heat shock proteins in immunotherapy.

Despite the significant advancements in cancer research, innovative approaches are still needed to reduce tumor incidence, progression, and dissemination, as well as for prolonging patient survival. Currently, the development of cancer vaccines is gaining attention as a novel preventative and therapeutic strategy. Although the concept of cancer vaccination is not new, a limited number of vaccines have received approval for tumor therapy. Heat shock protein (HSP)-based vaccination represents a promising strategy that harnesses specific tumor antigens to activate immune responses. Exosomes (Exs) are highly heterogeneous bilayer vesicles capable of transporting various types of molecules through extracellular space. Compared with conventional anticancer drugs, exosomes exhibit low toxicity and good biocompatibility, and they can stimulate the immune system either directly or indirectly. Ex-based vaccines may elicit an antitumor immune response that generates memory cells capable of recognizing cancer antigens, thereby inhibiting disease progression. This paper reviews the potential applications of HSPs and exosomes in the prevention and treatment of solid tumors. Finally, we discuss the advantages of the extracellular exosomal heat shock protein (HSP-Ex) vaccine and future research directions aimed at optimizing heat shock protein-based cancer immunotherapy strategies.

Recent Advances in Peptide-Loaded PLGA Nanocarriers for Drug Delivery and Regenerative Medicine.

Peptide-loaded poly(lactide-co-glycolide) (PLGA) nanocarriers represent a transformative approach to addressing the challenges of peptide-based therapies. These systems offer solutions to peptide instability, enzymatic degradation, and limited bioavailability by providing controlled release, targeted delivery, and improved stability. The versatility of PLGA nanocarriers extends across therapeutic domains, including cancer therapy, neurodegenerative diseases, vaccine development, and regenerative medicine. Innovations in polymer chemistry, surface functionalization, and advanced manufacturing techniques, such as microfluidics and electrospraying, have further enhanced the efficacy and scalability of these systems. This review highlights the key physicochemical properties, preparation strategies, and proven benefits of peptide-loaded PLGA systems, emphasizing their role in sustained drug release, immune activation, and tissue regeneration. Despite remarkable progress, challenges such as production scalability, cost, and regulatory hurdles remain.

In Silico-Guided Discovery of Polysaccharide Derivatives as Adjuvants in Nanoparticle Vaccines for Cancer Immunotherapy.

Cancer vaccines utilizing nanoparticle (NP) structures that integrate antigens and adjuvants to enhance delivery and stimulate immune responses are emerging as a promising avenue in cancer immunotherapy. However, the development of cancer vaccines has been significantly hindered by the low immunogenicity of tumor antigens. To address this challenge, substantial efforts have been made in developing innovative adjuvants to elicit effective immune responses. In this study, we develop a NP cancer vaccine assisted by a polysaccharide derivative adjuvant, designed through a computational strategy, to evoke effective antigen-specific antitumor immunity. Using TLR4 as the putative receptor, we conducted a comprehensive evaluation of a prescreening library consisting of 34 inulin derivatives through docking and molecular dynamics simulation. Consequently, a new derivative, benzoylated inulin (InBz), is selected as the most promising TLR4 agonist. The adjuvant effect of InBz is evaluated by fabricating InBz NPs encapsulating the model antigen ovalbumin (OVA). In vitro, InBz-OVA NPs effectively activate the TLR4 signaling pathways and facilitate dendritic cell maturation, thereby enhancing the antigen delivery and presentation. In vivo, InBz-OVA NPs outperform a commercial aluminum-based adjuvant, elicit robust antibody titers, induce antigen-specific cytotoxic T lymphocytes, and achieve significant tumor suppression in murine models. Besides, the adjuvant effects of other representative derivatives, namely, acetylated and chloroacetylated inulin, with moderate and low potential from the library, are also chemically synthesized and experimentally evaluated and found to be in agreement with computational predictions, confirming the credibility of the strategy. This study provides an effective platform for the pursuit of efficient polysaccharide-based vaccine adjuvants.

Innovative Strategies in Oncology: Bacterial Membrane Vesicle-Based Drug Delivery Systems for Cancer Diagnosis and Therapy.

Outer membrane vesicles (OMVs) are double-layered structures of nanoscale lipids released by gram-negative bacteria. They have the same membrane composition and characteristics as primitive cells, which enables them to penetrate cells and tissues efficiently. These OMVs exhibit excellent membrane stability, immunogenicity, safety, and permeability (which makes it easier for them to penetrate into tumour tissue), making them suitable for developing cancer vaccines and drug delivery systems. Recent studies have focused on engineering OMVs to enhance tumour-targeting capabilities, reduce toxicity, and extend circulation time in vivo. This article reviews the latest progress in OMV engineering for tumour treatment and discusses the challenges associated with the use of OMV-based antitumour therapy in clinical practice.

Chemoenzymatic liquid-phase synthesis and immunogenic assessment of tumor-associated complex MUC1 glycopeptide variants.

Aberrantly glycosylated Mucin 1 (MUC1) is frequently over-expressed in epithelial cancers, making it an attractive target for cancer vaccines. Over the past two decades, multiple MUC1-based vaccines have been investigated clinically, yet they have generally shown limited efficacy due to challenges such as low immunogenicity, difficulty in overcoming immune tolerance, and potential issues related to glycosylation effects and antigen presentations. To advance the understanding of MUC1 vaccines, we report an efficient chemo-enzymatic approach for the preparation of four MUC1 antigen variants with different glycoforms through liquid-phase glycopeptide synthesis. These antigen were conjugated with CRM197 to generate various glycopeptide-protein conjugate vaccines, and their immunogenicity was evaluated based on total and subtype antibody titers, binding affinity, complement-dependent cytotoxicity (CDC) activity, and antibody-dependent cellular phagocytosis (ADCP). The combination of MPL and QS21 adjuvants with STn-MUC1-CRM197 conjugate induced a potent Th1-biased immune response, evidenced by elevating IgG2a titers and stronger antibody binding to MCF-7 cells. This formulation demonstrated superior CDC activity, ADCP activity and binding affinity to human breast cancer tissues in immuno-histochemical assays. The synergistic effect of specific adjuvants and glycosylated MUC1 conjugates offers a strategic avenue for MUC1 cancer vaccine development.

Potent prophylactic cancer vaccines harnessing surface antigens shared by tumour cells and induced pluripotent stem cells.

The development of prophylactic cancer vaccines typically involves the selection of combinations of tumour-associated antigens, tumour-specific antigens and neoantigens. Here we show that membranes from induced pluripotent stem cells can serve as a tumour-antigen pool, and that a nanoparticle vaccine consisting of self-assembled commercial adjuvants wrapped by such membranes robustly stimulated innate immunity, evaded antigen-specific tolerance and activated B-cell and T-cell responses, which were mediated by epitopes from the abundant number of antigens shared between the membranes of tumour cells and pluripotent stem cells. In mice, the vaccine elicited systemic antitumour memory T-cell and B-cell responses as well as tumour-specific immune responses after a tumour challenge, and inhibited the progression of melanoma, colon cancer, breast cancer and post-operative lung metastases. Harnessing antigens shared by pluripotent stem cell membranes and tumour membranes may facilitate the development of universal cancer vaccines.

Recent Development of Cancer Vaccines

Immunotherapy, a truly innovative method in the field of cancer treatment, has attracted a great deal of attention because of its potential to bring about a revolution in the outcomes of cancer therapies. Even though there are many different ways being studied to make immunotherapy even more effective, fully realizing its potential, especially when it comes to cancer vaccines, is still a difficult goal to achieve. This review goes into detail about the different types of cancer vaccines, explaining the basic biological processes behind them and how they work with the immune system to fight cancer. We divide cancer vaccines into three main groups: virus-like particle (VLP) vaccines, peptide vaccines, and DNA/mRNA vaccines. Furthermore, this review also covers how these vaccines are being used in a wide range of infectious diseases and cancer types, emphasizing their versatility and the potential positive effects they can have on patients. Additionally, important topics related to the future of cancer vaccination are discussed, such as new ways to store vaccines to keep them effective, ways to reduce safety concerns, and the creation of personalized vaccines that are tailored to each patient's specific needs and cancer characteristics. By facing these challenges head-on and embracing the latest technologies, we hope to fully unlock the power of cancer vaccines, pushing the boundaries of cancer immunotherapy even further.

The Landmark Series: Cancer Vaccines for Solid Tumors.

Immunotherapy has become an integral part of the treatment for solid tumors. Cancer vaccines represent a potentially powerful class of immunotherapeutic agents to drive antitumor immunity. Cancer vaccine development involves selecting immunogenic target antigens expressed by tumor cells that can be effectively delivered for uptake by antigen-presenting cells to generate a robust adaptive immune response against tumor. While numerous cancer vaccines have been shown to produce antigen-specific immune responses, translating promising results of immunogenicity from early-phase trials into durable clinical benefit in larger randomized trials has remained elusive. Recent findings support new enthusiasm for several cancer vaccine approaches for solid tumors. This review will discuss landmark historic clinical trials in cancer vaccine development and strategies to optimize cancer vaccines to achieve improved clinical efficacy.

Rational Design of an Epidermal Growth Factor Receptor Vaccine: Immunogenicity and Antitumor Research.

The epidermal growth factor receptor (EGFR) is frequently overexpressed in a variety of human epithelial tumors, and its aberrant activation plays a pivotal role in promoting tumor growth, invasion, and metastasis. The clinically approved passive EGFR-related therapies have numerous limitations. Seven EGFR-ECD epitope peptides (EG1-7) were selected through bioinformatics epitope prediction tools including NetMHCpan-4.1, NetMHCIIpan-3.2, and IEDB Consensus (v2.18 and v2.22) and fused to the translocation domain of diphtheria toxin (DTT). The A549 tumor model was successfully established in a murine mouse model. The vaccine was formulated by combining the adjuvants Alum and CpG and subsequently assessed for its immunogenicity and anti-tumor efficacy. DTT-EG (3;5;6;7) vaccines elicited specific humoral and cellular immune responses and effectively suppressed tumor growth in both prophylactic and therapeutic mouse tumor models. The selected epitopes EG3 (HGAVRFSNNPALCNV145-159), EG5 (KDSLSINATNIKHFK346-360), EG6 (VKEITGFLLIQAWPE398-412), and EG7 (LCYANTINWKKLFGT469-483) were incorporated into vaccines for active immunization, representing a promising strategy for the treatment of tumors with overexpressed epidermal growth factor receptor (EGFR). The vaccine design and fusion method employed in this study demonstrate a viable approach toward the development of cancer vaccines.

VaxOptiML: leveraging machine learning for accurate prediction of MHC-I and II epitopes for optimized cancer immunotherapy.

Cancer immunotherapy hinges on accurate epitope prediction for advancing vaccine development. VaxOptiML (available at https://vaxoptiml.streamlit.app/ ) is an integrated pipeline designed to enhance epitope prediction and prioritization. This study aims to develop and deploy a robust tool for accurate prediction and prioritization of highly immunogenic and optimized MHC-I and MHC-II T-cell epitopes for cancer vaccine development and immunotherapy. Utilizing a curated dataset of experimentally validated epitopes and employing sophisticated machine learning techniques, VaxOptiML features three models: epitope prediction from target sequences, personalized HLA typing, and prioritizationthe predicted epitopesbased on immunogenicity scores. Our rigorous data extraction, cleaning, and feature extraction processes, coupled with model building, yield exceptional accuracy, sensitivity, specificity, and F1 score, surpassing existing prediction methods. Comprehensive visual representations underscore VaxOptiML's robustness and efficacy in accelerating epitope discovery and vaccine design for cancer immunotherapy. Deployed via Streamlit for public use, VaxOptiML enhances accessibility and usability for researchers and clinicians, demonstrating significant potential in cancer immunotherapy.

The Glycopeptide PV-PS A1 Immunogen Elicits Both CD4+ and CD8+ Responses.

The MHCII-dependent, CD4+ T-cell zwitterionic polysaccharide PS A1 has been investigated as a promising carrier for vaccine development because it can induce an MHCII-dependent CD4+ response towards a variety of tumor-associated carbohydrate antigens (TACAs). However, PS A1 cannot elicit cytotoxic T lymphocytes through MHCI, which may or may not hamper its potential clinical use in cancer, infectious and viral vaccine development. This paper addresses PS A1 MHCI independence through the introduction of an MHCI epitope, the poliovirus (PV) peptide, to establish an MHCI- and MHCII-dependent vaccine. We synthesized a glycopeptide construct targeting the Thomsen-nouveau TACA (Tn-PV-PS A1) and a control Tn-PV peptide. C57BL/6 mice were immunized with both constructs, and the resulting T-cells were extracted from spleens. Through cell proliferation assays, we show that Tn-PV-PS A1 elicits a robust CD4+ and CD8+ immune response. The resulting cytotoxic T lymphocytes are specific towards Tn-PV and trigger cell lysis of Tn-expressing EL4 cells. This study confirms PV-PS A1 as a robust MHCI- and MHCII-dependent carrier. This is the first report of MHCI dependence in a zwitterionic polysaccharide.

Localized In Vivo Electro Gene Therapy (LiveGT)-Mediated Skeletal Muscle Protein Factory Reprogramming

Gene electrotransfer (GET) has gained significant momentum as a non-viral gene delivery method for various clinical applications, primarily in the cancer immunotherapy and vaccine development space. Preclinical studies have demonstrated exogenous gene delivery and expression in various tissues, including the liver, skin, cardiac muscle, and skeletal muscle. However, protein replacement applications of this technology have yet to be fully actuated. Plasmid DNA skeletal muscle delivery has been shown to maintain expression for up to 18 months. In the current study, we evaluated localized skeletal muscle delivery for protein replacement applications. We developed localized in vivo electro gene therapy (liveGT) protocols utilizing mono- and biphasic pulse sequences for localized pulse delivery directly to skeletal muscle with a custom monopolar platinum electrode. Plasmid DNA encoding human insulin and human glucokinase were chosen for this study to evaluate the liveGT platform for protein replacement potential. Initial in vitro GET was performed in mouse myoblasts to evaluate human insulin and glucokinase co-delivery. This was followed by liveGT-mediated reporter gene delivery in the skeletal muscle of Sprague–Dawley rats for pulse sequence selection. Protein replacement potential was evaluated in healthy (non-diabetic) rats with liveGT-mediated human insulin and glucokinase co-delivery to skeletal muscle. Human and rat insulin levels were measured via ELISA over the course of 3 months. Fed-state blood glucose measurements were monitored in correlation with serum human insulin levels. LiveGT-mediated skeletal muscle reprogramming successfully produced physiological levels of human insulin in serum over the course of 3 months. Hypo- and hyperglycemic events were not observed. Therefore, liveGT is a safe and viable platform for potential protein replacement therapies.

Adenoviral-vectored neoantigen vaccine augments hyperexpanded CD8+ T cell control of tumor challenge in mice

BackgroundNeoantigens are promising immunogens for cancer vaccines and are often delivered as adjuvanted peptide vaccines. Adenoviral (Ad) vectors have been shown to induce strong CD8+ T cell responses as vaccines...

Challenges and New Directions in Therapeutic Cancer Vaccine Development.

Tumor vaccine is a promising immunotherapy for solid tumors. Therapeutic tumor vaccines aim at inducing tumor regression, establishing durable antitumor memory, and avoiding non-specific or adverse reactions. However, tumor-induced immune suppression and immune resistance pose challenges to achieving this goal. In this article, we review multiple challenges currently faced in the development of therapeutic tumor vaccines, with a particular focus on anonymous antigen vaccines in situ as a new direction. We summarize the research progress in this area, aiming to provide a reference for future studies on tumor vaccines.

Molecular basis for chemokine recognition and activation of XCR1

The X-C motif chemokine receptor XCR1, which selectively binds to the chemokine XCL1, is highly expressed in conventional dendritic cells subtype 1 (cDC1s) and crucial for their activation. Modulating XCR1 signaling in cDC1s could offer novel opportunities in cancer immunotherapy and vaccine development by enhancing the antigen presentation function of cDC1s. To investigate the molecular mechanism of XCL-induced XCR1 signaling, we determined a high-resolution structure of the human XCR1 and Gi complex with an engineered form of XCL1, XCL1 CC3, by cryoelectron microscopy. Through mutagenesis and structural analysis, we elucidated the molecular details for the binding of the N-terminal segment of XCL1 CC3, which is vital for activating XCR1. The unique arrangement within the XCL1 CC3 binding site confers specificity for XCL1 in XCR1. We propose an activation mechanism for XCR1 involving structural alterations of key residues at the bottom of the XCL1 binding pocket. These detailed insights into XCL1 CC3-XCR1 interaction and XCR1 activation pave the way for developing novel XCR1-targeted therapeutics.

Vaccine Therapies for Cancer: Challenges and Strategies

Abstract. As oncology vaccines have become more effective in clinical trials, it has become clear that they have great potential to attack malignant tumors in the future. Even though oncology vaccines are now a minor success and most of the cancer vaccines in the market are prophylactic rather than therapeutic for malignant tumors, cancer vaccines are still in the limelight and a lot of research has been invested in this area. From the time that tumor vaccines were noticed and researched to the present day, they have always faced difficulties, which has led to no breakthrough in cancer vaccines for a long time. Nowadays, only a small percentage of cancer vaccines have been put into clinical use despite the tireless efforts of people. There is still a lot of room for progress in cancer vaccines, and this paper goes through the development, types, and mechanisms of cancer vaccines to understand the advantages and disadvantages of cancer vaccines and analyze the challenges and strategies of cancer vaccines.

Abstract B001: CircRNA-derived neoantigen identification in cancer vaccine development

Abstract Immunotherapy has been a popular topic in combating cancer for its great performance in specificity, versatility and durability recently. Cancer vaccines targeting neoantigens have shown clinical efficacy against cancer, eliciting long-lasting immune response and offering a more selective therapeutic approach with less side effects. However, rare mutation rates and low expression levels of neoantigen make it challenging to identify suitable neoantigens. Traditionally, researchers focus on the canonical mRNA transcriptome and proteome to find potential targets. Recent studies suggest that exploring the non-canonical transcriptome and proteome, particularly circular RNAs (circRNAs), can expand the search. CircRNAs, endogenously formed by the unique back-splicing events during pre-RNA processing, can serve as templates for protein synthesis. Some of these non-canonical peptides are specifically expressed in cancer cells, making circRNAs a valid source for neoantigen discovery. We have developed high-throughput circRNA reporter screening methods and mass spectrometry-based peptidomic workflow to pinpoint translating circRNAs and their derived peptides. Using these techniques, we have identified circRNA-derived neoantigens in breast cancer (BC) cell lines that can be used as possible targets for cancer vaccines. These circRNA-derived neoantigens are immunogenic and can trigger dendritic cell (DC) maturation and T cell activation in vitro. Next, we will test these findings by transferring to in vivo mouse system. We will assess cancer vaccine efficacy by targeting the neoantigens using syngeneic mouse tumor models. Our long- term goal is to apply the circRNA neoantigen identification technology to BC patient samples to facilitate cancer vaccine development and improve cancer immunotherapy. Our work will demonstrate the potential of circRNA-derived non canonical neoantigens in cancer vaccines, serving as a crucial first step to prove their effectiveness in therapy. By expanding our search beyond the traditional transcriptome and proteome, we will explore new targets and transform the neoantigen-based treatment. This innovative effort shifts the current understanding of neoantigen sources and opens up new possibilities for targeted cancer therapy strategies. Citation Format: Yi-Cian Zheng, Chun-Kan Chen. CircRNA-derived neoantigen identification in cancer vaccine development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B001.