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Cancer vaccines have been developed as a promising way to boost cancer immunity. However, their clinical potency is often limited due to the imprecise delivery of tumor antigens. To overcome this problem, we conjugated an endogenous Toll-like receptor (TLR)2/6 ligand, UNE-C1, to human papilloma virus type 16 (HPV-16)-derived peptide antigen, E7, and found that the UNE-C1-conjugated cancer vaccine (UCV) showed significantly enhanced antitumor activity in vivo compared with the noncovalent combination of UNE-C1 and E7. The combination of UCV with PD-1 blockades further augmented its therapeutic efficacy. Specifically, the conjugation of UNE-C1 to E7 enhanced its retention in inguinal draining lymph nodes, the specific delivery to dendritic cells and E7 antigen-specific T cell responses, and antitumor efficacy in vivo compared with the noncovalent combination of the two peptides. These findings suggest the potential of UNE-C1 derived from human cysteinyl-tRNA synthetase 1 as a unique vehicle for the specific delivery of cancer antigens to antigen-presenting cells via TLR2/6 for the improvement of cancer vaccines.

BACKGROUND AND OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is 3rd most lethal cancer in the USA leading to a median survival of six months and less than 5% 5-year overall survival (OS). As the only potentially curative treatment, surgical resection is not suitable for up to 90% of the patients with PDAC due to late diagnosis. Highly fibrotic PDAC with an immunosuppressive tumor microenvironment restricts cytotoxic T lymphocyte (CTL) infiltration and functions causing limited success with systemic therapies like dendritic cell (DC)-based immunotherapy. In this study, we investigated the potential benefits of irreversible electroporation (IRE) ablation therapy in combination with DC vaccine therapy against PDAC. METHODS: We performed a literature search to identify studies focused on DC vaccine therapy and IRE ablation to boost therapeutic response against PDAC indexed in PubMed, Web of Science, and Scopus until February 20th, 2023. KEY CONTENT AND FINDINGS: IRE ablation destructs tumor structure while preserving extracellular matrix and blood vessels facilitating local inflammation. The studies demonstrated IRE ablation reduces tumor fibrosis and promotes CTL tumor infiltration to PDAC tumors in addition to boosting immune response in rodent models. The administration of the DC vaccine following IRE ablation synergistically enhances therapeutic response and extends OS rates compared to the use of DC vaccination or IRE alone. Moreover, the implementation of data-driven approaches further allows dynamic and longitudinal monitoring of therapeutic response and OS following IRE plus DC vaccine immunoablation. CONCLUSIONS: The combination of IRE ablation and DC vaccine immunotherapy is a potent strategy to enhance the therapeutic outcomes in patients with PDAC.

Nucleic acid vaccines have emerged as crucial advancements in vaccine technology, particularly highlighted by the global response to the COVID-19 pandemic. The widespread administration of mRNA vaccines against COVID-19 to billions globally marks a significant milestone. Furthermore, the approval of an mRNA vaccine for Respiratory Syncytial Virus (RSV) this year underscores the versatility of this technology. In oncology, the combination of mRNA vaccine encoding neoantigens and immune checkpoint inhibitors (ICIs) has shown remarkable efficacy in eliciting protective responses against diseases like melanoma and pancreatic cancer. Although the use of a COVID-19 DNA vaccine has been limited to India, the inherent stability at room temperature and cost-effectiveness of DNA vaccines present a viable option that could benefit developing countries. These advantages may help DNA vaccines address some of the challenges associated with mRNA vaccines. Currently, several trials are exploring the use of DNA-encoded neoantigens in combination with ICIs across various cancer types. These studies highlight the promising role of nucleic acid-based vaccines as the next generation of immunotherapeutic agents in cancer treatment. This review will delve into the recent advancements and current developmental status of both mRNA and DNA-based cancer vaccines. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, there has been a paradigm shift in first-line treatment for unresectable hepatocellular carcinoma (HCC) from multitargeted tyrosine kinase inhibitors to immune checkpoint inhibitor-based therapies. Despite the unprecedented improvement in clinical outcomes, responses to these therapies are still only observed in a minority of HCC patients. In this review, we discuss the tumor intrinsic and extrinsic mechanisms of resistance to standard immune checkpoint inhibitors, explore novel approaches to optimize immunotherapy-based regimens, and highlight notable clinical trials that have the potential to change future standard care for HCC. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15–20% of HCC patients being suitable for potentially curative treatments, the vast majority of patients with HCC ultimately require systemic therapy. For decades, the choice of effective systemic therapy for HCC remained sparse. In recent years, after the combination of atezolizumab and bevacizumab demonstrated superior overall survival over the first-line standard, sorafenib, there has been a major therapeutic paradigm shift to immunotherapy-based regimens for HCC. While representing a great leap forward for the treatment of this cancer, the reality is that less than one-third of patients achieve an objective response to immune checkpoint inhibitor-based therapy, so there remains a significant clinical need for further therapeutic optimization. In this review, we provide an overview of the current landscape of immunotherapy for unresectable HCC and delve into the tumor intrinsic and extrinsic mechanisms of resistance to established immunotherapies with a focus on novel therapeutic targets with strong translational potential. Following this, we spotlight emerging immunotherapy approaches and notable clinical trials aiming to optimize immunotherapy efficacy in HCC that include novel immune checkpoint inhibitors, tumor microenvironment modulators, targeted delivery systems, and locoregional interventions. [ABSTRACT FROM AUTHOR]

Cancer vaccines are promising as an effective means of stimulating the immune system to clear tumors as well as to establish immune surveillance. In this paper, we discuss the main platforms and current status of cancer vaccines and propose a new cancer vaccine platform, the cytosolic vesicle vaccine. This vaccine has a unique structure that can integrate antigen and adjuvant carriers to improve the delivery efficiency and immune activation ability, which brings new ideas for cancer vaccine design. Tumor exosomes carry antigens and MHC-peptide complexes, which can provide tumor antigens to antigen-processing cells and increase the chances of recognition of tumor antigens by immune cells. DEVs play a role in amplifying the immune response by acting as carriers for the dissemination of antigenic substances in dendritic cells. OMVs, with their natural adjuvant properties, are one of the advantages for the preparation of antitumor vaccines. This paper presents the advantages of these three bacteria/extracellular vesicles as cancer vaccines and discusses the potential applications of functionally modified extracellular vesicles as cancer vaccines after cellular engineering or genetic engineering, as well as current clinical trials of extracellular vesicle vaccines. In summary, extracellular vesicle vaccines are a promising direction for cancer vaccine research. [ABSTRACT FROM AUTHOR]

Cancer vaccines, crucial in the immunotherapeutic landscape, are bifurcated into preventive and therapeutic types, both integral to combating oncogenesis. Preventive cancer vaccines, like those against HPV and HBV, reduce the incidence of virus-associated cancers, while therapeutic cancer vaccines aim to activate dendritic cells and cytotoxic T lymphocytes for durable anti-tumor immunity. Recent advancements in vaccine platforms, such as synthetic peptides, mRNA, DNA, cellular, and nano-vaccines, have enhanced antigen presentation and immune activation. Despite the US Food and Drug Administration approval for several vaccines, the full therapeutic potential remains unrealized due to challenges such as antigen selection, tumor-mediated immunosuppression, and optimization of delivery systems. This review provides a comprehensive analysis of the aims and implications of preventive and therapeutic cancer vaccine, the innovative discovery of neoantigens enhancing vaccine specificity, and the latest strides in vaccine delivery platforms. It also critically evaluates the role of adjuvants in enhancing immunogenicity and mitigating the immunosuppressive tumor microenvironment. The review further examines the synergistic potential of combining cancer vaccines with other therapies, such as chemotherapy, radiotherapy, and immune checkpoint inhibitors, to improve therapeutic outcomes. Overcoming barriers such as effective antigen identification, immunosuppressive microenvironments, and adverse effects is critical for advancing vaccine development. By addressing these challenges, cancer vaccines can offer significant improvements in patient outcomes and broaden the scope of personalized cancer immunotherapy. [ABSTRACT FROM AUTHOR]

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 endcapped 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. [ABSTRACT FROM AUTHOR]

Summary Epithelial cell adhesion molecule (EpCAM) fused to IgG, IgA and IgM Fc domains was expressed to create IgG, IgA and IgM‐like structures as anti‐cancer vaccines in Nicotiana tabacum. High‐mannose glycan structures were generated by adding a C‐terminal endoplasmic reticulum (ER) retention motif (KDEL) to the Fc domain (FcK) to produce EpCAM‐Fc and EpCAM‐FcK proteins in transgenic plants via Agrobacterium‐mediated transformation. Cross‐fertilization of EpCAM‐Fc (FcK) transgenic plants with Joining chain (J‐chain, J and JK) transgenic plants led to stable expression of large quaternary EpCAM‐IgA Fc (EpCAM‐A) and IgM‐like (EpCAM‐M) proteins. Immunoblotting, SDS–PAGE and ELISA analyses demonstrated that proteins with KDEL had higher expression levels and binding activity to anti‐EpCAM IgGs. IgM showed the strongest binding among the fusion proteins, followed by IgA and IgG. Sera from BALB/c mice immunized with these vaccines produced anti‐EpCAM IgGs. Flow cytometry indicated that the EpCAM‐Fc fusion proteins significantly activated CD8+ cytotoxic T cells, CD4+ helper T cells and B cells, particularly with EpCAM‐FcKP and EpCAM‐FcP (FcKP) × JP (JKP). The induced anti‐EpCAM IgGs captured human prostate cancer PC‐3 and colorectal cancer SW620 cells. Sera from immunized mice inhibited cancer cell proliferation, migration and invasion; down‐regulated proliferation markers (PCNA, Ki‐67) and epithelial–mesenchymal transition markers (Vimentin); and up‐regulated E‐cadherin. These findings suggest that N. tabacum can produce effective vaccine candidates to induce anti‐cancer immune responses. [ABSTRACT FROM AUTHOR]

Decades of basic and translational research have led to a momentum shift in dissecting the relationship between immune cells and cancer. This culminated in the emergence of breakthrough immunotherapies that paved the way for oncologists to manage certain hard-to-treat cancers. The application of high-throughput techniques of genomics, transcriptomics, and proteomics was conclusive in making and expediting the manufacturing process of cancer vaccines. Using the latest research technologies has also enabled scientists to interpret complex and multiomics data of the tumour mutanome, thus identifying new tumour-specific antigens to design new generations of cancer vaccines with high specificity and long-term efficacy. Furthermore, combinatorial regimens of cancer vaccines with immune checkpoint inhibitors have offered new therapeutic approaches and demonstrated impressive efficacy in cancer patients over the last few years. In the present review, we summarize the current state of cancer vaccines, including their potential therapeutic effects and the limitations that hinder their effectiveness. We highlight the current efforts to mitigate these limitations and highlight ongoing clinical trials. Finally, a special focus will be given to the latest milestones expected to transform the landscape of cancer therapy and nurture hope among cancer patients. [ABSTRACT FROM AUTHOR]

Malignant melanoma, a rapidly spreading form of skin cancer, is becoming more prevalent worldwide. While surgery is successful in treating early-stage melanoma, patients with advanced disease have only a 20 % chance of surviving beyond five years. Melanomas with mutations in the NRAS gene are characterized for a more aggressive tumor biology, poorer prognosis and shorter survival. Hence, new therapeutic strategies are needed, especially for this specific group of patients. Novel approaches, such as cancer vaccines, offer promising solutions by stimulating the anti-tumor immune response. Nevertheless, their clinical efficacy is still modest and more effective approaches are required. Herein, we propose the systemic administration of the adenovirus-based cancer vaccine complexed in extracellular vesicles (EVs) with the aim of achieving a targeted therapeutic effect. The vaccine was based on previously tested oncolytic adenovirus Ad5/3-D24-ICOSL-CD40L in combination with melanoma-specific antigens targeting NRAS mutations to enhance the anticancer effect. The antineoplastic properties of the oncolytic vaccine were evaluated in xenograft MUG Mel-2 melanoma BALB/c nude mice. Moreover, to mimic the tumor microenvironment, while investigating at the same time immune cell infiltration and drug penetration, we established a 3D co-culture model based on human NRAS mutated MUG Mel-2 spheroids and PBMCs (HLA matched), which displayed a synergistic effect when treated with the cancer vaccine compared to relative controls. Subsequently, we investigated the systemic delivery of the vaccine in EV formulations in a humanized NSG MUG Mel-2 melanoma mouse model. Our study provides a promising strategy for a tumor-targeted vaccine delivery by EVs, resulting in improved anticancer efficacy and increased infiltration of tumor-infiltrating lymphocytes. This study explores the potential of EVs for the selective delivery of cancer vaccines against malignancies, such as NRAS melanoma. Overall, this research could pave the way for applying autologous EVs as a safe and efficacious tool for targeted cancer therapy. [Display omitted] • EVs enhance the targeted delivery of the oncolytic vaccine to the tumor. • EVs as a tool for systemic delivery of oncolytic vaccine for melanoma treatment. • EVs as a strategy for treating both primary and metastatic melanoma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Because therapeutic cancer vaccines can, in theory, eliminate tumor cells specifically with relatively low toxicity, they have long been considered for application in repressing cancer progression. Traditional cancer vaccines containing a single or a few discrete tumor epitopes have failed in the clinic, possibly due to challenges in epitope selection, target downregulation, cancer cell heterogeneity, tumor microenvironment immunosuppression, or a lack of vaccine immunogenicity. Whole cancer cell or cancer membrane vaccines, which provide a rich source of antigens, are emerging as viable alternatives. Autologous and allogenic cellular cancer vaccines have been evaluated as clinical treatments. Tumor cell membranes (TCMs) are an intriguing antigen source, as they provide membrane‐accessible targets and, at the same time, serve as integrated carriers of vaccine adjuvants and other therapeutic agents. This review provides a summary of the properties and technologies for TCM cancer vaccines. Characteristics, categories, mechanisms, and preparation methods are discussed, as are the demonstrable additional benefits derived from combining TCM vaccines with chemotherapy, sonodynamic therapy, phototherapy, and oncolytic viruses. Further research in chemistry, biomedicine, cancer immunology, and bioinformatics to address current drawbacks could facilitate the clinical adoption of TCM vaccines. [ABSTRACT FROM AUTHOR]

Abstract Cancer vaccines are promising as an effective means of stimulating the immune system to clear tumors as well as to establish immune surveillance. In this paper, we discuss the main platforms and current status of cancer vaccines and propose a new cancer vaccine platform, the cytosolic vesicle vaccine. This vaccine has a unique structure that can integrate antigen and adjuvant carriers to improve the delivery efficiency and immune activation ability, which brings new ideas for cancer vaccine design. Tumor exosomes carry antigens and MHC-peptide complexes, which can provide tumor antigens to antigen-processing cells and increase the chances of recognition of tumor antigens by immune cells. DEVs play a role in amplifying the immune response by acting as carriers for the dissemination of antigenic substances in dendritic cells. OMVs, with their natural adjuvant properties, are one of the advantages for the preparation of antitumor vaccines. This paper presents the advantages of these three bacteria/extracellular vesicles as cancer vaccines and discusses the potential applications of functionally modified extracellular vesicles as cancer vaccines after cellular engineering or genetic engineering, as well as current clinical trials of extracellular vesicle vaccines. In summary, extracellular vesicle vaccines are a promising direction for cancer vaccine research.

Abstract Cancer vaccines, crucial in the immunotherapeutic landscape, are bifurcated into preventive and therapeutic types, both integral to combating oncogenesis. Preventive cancer vaccines, like those against HPV and HBV, reduce the incidence of virus-associated cancers, while therapeutic cancer vaccines aim to activate dendritic cells and cytotoxic T lymphocytes for durable anti-tumor immunity. Recent advancements in vaccine platforms, such as synthetic peptides, mRNA, DNA, cellular, and nano-vaccines, have enhanced antigen presentation and immune activation. Despite the US Food and Drug Administration approval for several vaccines, the full therapeutic potential remains unrealized due to challenges such as antigen selection, tumor-mediated immunosuppression, and optimization of delivery systems. This review provides a comprehensive analysis of the aims and implications of preventive and therapeutic cancer vaccine, the innovative discovery of neoantigens enhancing vaccine specificity, and the latest strides in vaccine delivery platforms. It also critically evaluates the role of adjuvants in enhancing immunogenicity and mitigating the immunosuppressive tumor microenvironment. The review further examines the synergistic potential of combining cancer vaccines with other therapies, such as chemotherapy, radiotherapy, and immune checkpoint inhibitors, to improve therapeutic outcomes. Overcoming barriers such as effective antigen identification, immunosuppressive microenvironments, and adverse effects is critical for advancing vaccine development. By addressing these challenges, cancer vaccines can offer significant improvements in patient outcomes and broaden the scope of personalized cancer immunotherapy.

Abstract Immuno-oncology has witnessed remarkable advancements in the past decade, revolutionizing the landscape of cancer therapeutics in an encouraging manner. Among the diverse immunotherapy strategies, mRNA vaccines have ushered in a new era for the therapeutic management of malignant diseases, primarily due to their impressive impact on the COVID-19 pandemic. In this comprehensive review, we offer a systematic overview of mRNA vaccines, focusing on the optimization of structural design, the crucial role of delivery materials, and the administration route. Additionally, we summarize preclinical studies and clinical trials to provide valuable insights into the current status of mRNA vaccines in cancer treatment. Furthermore, we delve into a systematic discussion on the significant challenges facing the current development of mRNA tumor vaccines. These challenges encompass both intrinsic and external factors that are closely intertwined with the successful application of this innovative approach. To pave the way for a more promising future in cancer treatments, a deeper understanding of immunological mechanisms, an increasing number of high-quality clinical trials, and a well-established manufacturing platform are crucial. Collaborative efforts between scientists, clinicians, and industry engineers are essential to achieving these goals.

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. [ABSTRACT FROM AUTHOR]

Abstract Cancer vaccines have garnered attention as a potential treatment for cancer metastases. Nevertheless, the clinical response rate to vaccines remains

Abstract Recent breakthroughs in cancer immunotherapies have emphasized the importance of harnessing the immune system for treating cancer. Vaccines, which have traditionally been used to promote protective immunity against pathogens, are now being explored as a method to target cancer neoantigens. Over the past few years, extensive preclinical research and more than a hundred clinical trials have been dedicated to investigating various approaches to neoantigen discovery and vaccine formulations, encouraging development of personalized medicine. Nucleic acids (DNA and mRNA) have become particularly promising platform for the development of these cancer immunotherapies. This shift towards nucleic acid-based personalized vaccines has been facilitated by advancements in molecular techniques for identifying neoantigens, antigen prediction methodologies, and the development of new vaccine platforms. Generating these personalized vaccines involves a comprehensive pipeline that includes sequencing of patient tumor samples, data analysis for antigen prediction, and tailored vaccine manufacturing. In this review, we will discuss the various shared and personalized antigens used for cancer vaccine development and introduce strategies for identifying neoantigens through the characterization of gene mutation, transcription, translation and post translational modifications associated with oncogenesis. In addition, we will focus on the most up-to-date nucleic acid vaccine platforms, discuss the limitations of cancer vaccines as well as provide potential solutions, and raise key clinical and technical considerations in vaccine development.

Ting-Wei Lin,1 Po-Yu Chou,2 Yen-Ting Shen,2 Ming-Thau Sheu,2 Kuo-Hsiang Chuang,3,4 Shyr-Yi Lin,5,6 Chia-Yi Chang1 1Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan; 2School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 3PhD Program in Clinical Drug Development of Chinese Herbal Medicine, Taipei Medical University, Taipei, Taiwan; 4Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; 6Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, TaiwanCorrespondence: Shyr-Yi Lin; Chia-Yi Chang, Email sylin@tmu.edu.tw; chiayichang@ntu.edu.twPurpose: Immunotherapy emerges as a promising frontier in cancer therapy and prevention. This study investigates the capacity of tumor-antigenic nanoparticles, specifically ovalbumin-tethered spiked virus-like poly(lactic-co-glycolic acid) nanoparticles (OVA-sVLNP), to effectively elicit humoral and cellular immune responses against tumors.Methods: OVA-sVLNP were synthesized through thiol-maleimide crosslinking using a single emulsion method. Comprehensive characterization was performed through Nuclear Magnetic Resonance (NMR), dynamic light scattering, Cryo-electron microscopy (Cryo-EM), confocal microscopy, and flow cytometry. Immunogenicity was evaluated using an enzyme-linked immunosorbent assay (ELISA) for quantifying immunoglobulin levels (IgG, IgG1, IgG2a) and cytokines in mouse sera. Flow cytometry profiled cellular immune responses in mouse spleens, and organ biosafety was assessed using immunohistochemistry and hematoxylin and eosin (H&E) staining.Results: OVA-sVLNP had a mean particle size of 193.8 ± 11.9 nm, polydispersity index of 0.307 ± 0.04, and zeta potential of − 39.6 ± 10.16 mV, remaining stable for one month at 4°C. In vitro studies revealed significant upregulation of CD80/CD86 in dendritic cells, indicating robust activation. In vivo, the optimal concentration (V25) induced potent IgG, IgG1, and IgG2a antibodies, significant populations of CD3+CD4+, CD3+CD8+, and a rare subset of CD3+CD4+CD8+ memory T cells. Notably, Th9 induction resulted in the secretion of IL-9, IL-10, and other cytokines, which are crucial for orchestrating cytotoxic T cell activity and antitumor effects. Overall, higher doses did not improve outcomes, highlighting the significance of optimal dosing.Conclusion: This study demonstrated potent immunogenicity of OVA-sVLNP, characterized by the induction of specific IgG antibodies and the stimulation of cellular immune responses, particularly tumor-killing Th9 cells. The simplicity and cost-effectiveness of the manufacturing process augment the potential of OVA-sVLNP as a viable candidate for antitumor vaccines, opening new avenues for cancer prevention and cell-based therapeutic strategies. Keywords: tumor antigen-spiked virus-like nanoparticles, PLGA nanoparticles, cancer vaccine, ovalbumin, T helper 9, antitumor

Abstract The malignant form of melanoma is one of the deadliest human cancers that accounts for almost all of the skin tumor-related fatalities in its later stages. Achieving an exhaustive understanding of reliable cancer-specific markers and molecular pathways can provide numerous practical techniques and direct the way toward the development of rational curative medicines to increase the lifespan of patients. Immunotherapy has significantly enhanced the treatment of metastatic and late-stage melanoma, resulting in an incredible increase in positive responses to therapy. Despite the increasing occurrence of melanoma, the median survival rate for patients with advanced, inoperable terminal disease has increased from around six months to almost six years. The current knowledge of the tumor microenvironment (TME) and its interaction with the immune system has resulted in the swift growth of innovative immunotherapy treatments. Exosomes are small extracellular vesicles (EVs), ranging from 30 to 150 nm in size, that the majority of cells released them. Exosomes possess natural advantages such as high compatibility with living organisms and low potential for causing immune reactions, making them practical for delivering therapeutic agents like chemotherapy drugs, nucleic acids, and proteins. This review highlights recent advancements in using exosomes as an approach to providing medications for the treatment of melanoma.

Cancer vaccines have garnered attention as a potential treatment for cancer metastases. Nevertheless, the clinical response rate to vaccines remains < 30%. Nanoparticles stabilize vaccines and improve antigen recognition and presentation, resulting in high tumor penetration or accumulation, effective co-distribution of drugs to the secondary lymphatic system, and adaptable antigen or adjuvant administration. Such vaccine-like nanomedicines have the ability to eradicate the primary tumors as well as to prevent or eliminate metastases. This review examines state-of-the-art nanocarriers developed to deliver tumor vaccines to metastases, including synthetic, semi-biogenic, and biogenic nanosystems. Moreover, it highlights the physical and pharmacological properties that enhance their anti-metastasis efficiency. This review also addresses the combination of nanovaccines with cancer immunotherapy to target various steps in the metastatic cascade, drawing insights from preclinical and clinical studies. The review concludes with a critical analysis of the challenges and frameworks linked to the clinical translation of cancer nanovaccines. [ABSTRACT FROM AUTHOR]

One driver of the high failure rates of clinical trials for therapeutic cancer vaccines is likely the inability to sufficiently engage conventional dendritic cells (cDCs), the antigen-presenting cell (APC) subset that is specialized in priming antitumor T cells. Here, we demonstrate that, relative to vaccination with an injectable mesoporous silica rod (MPS) vaccine alone (Vax), combining MPS vaccines with CD122-biased IL-2/anti-IL-2 antibody complexes (IL-2cx) drives ~3-fold expansion of cDCs at the vaccination sites, vaccine-draining lymph nodes, and spleens of treated mice. Furthermore, relative to Vax alone, Vax+IL-2cx led to a ~3-fold increase in the numbers of CD8+ T cells and ~15-fold increase in the numbers of NK cells at the vaccination site. Notably, with both the model protein antigen OVA as well as various peptide neoantigens, Vax+IL-2cx induced ~5 to 30-fold greater numbers of circulating antigen-specific CD8+ T cells relative to Vax alone. We further demonstrate that Vax+IL-2cx leads to significantly improved efficacy in the MC38 colon carcinoma model relative to either monotherapy alone, driving complete regressions in 50% of mice in a cDC-dependent manner. Relative to vaccine alone, Vax+IL-2cx led to comparable numbers of CD8+ T cells, but markedly greater numbers of NK cells and activated cDCs in the B16F10 melanoma tumor microenvironment post-therapy. Taken together, these findings suggest that the administration of factors that engage both the cDC-CD8+ T cell and cDC-NK cell axes can boost the potency of therapeutic cancer vaccines. [ABSTRACT FROM AUTHOR]

Somatic mutations in tumor cells give rise to mutant proteins, fragments of which are often presented by MHC and serve as neoantigens. Neoantigens are tumor-specific and not expressed in healthy tissues, making them attractive targets for T-cell-based cancer immunotherapy. On the other hand, since most somatic mutations differ from patient to patient, neoantigen-targeted immunotherapy is personalized medicine and requires their identification in each patient. Computational algorithms and machine learning methods have been developed to prioritize neoantigen candidates. In fact, since the number of clinically relevant neoantigens present in a patient is generally limited, this process is like finding a needle in a haystack. Nevertheless, MHC presentation of neoantigens is not random but follows certain rules, and the efficiency of neoantigen detection may be further improved with technological innovations. In this review, we discuss current approaches to the detection of clinically relevant neoantigens, with a focus on antigen processing and presentation. [ABSTRACT FROM AUTHOR]

Immunotherapy has ushered in a new era of cancer treatment, yet cancer remains a leading cause of global mortality. Among various therapeutic strategies, cancer vaccines have shown promise by activating the immune system to specifically target cancer cells. While current cancer vaccines are primarily prophylactic, advancements in targeting tumor-associated antigens (TAAs) and neoantigens have paved the way for therapeutic vaccines. The integration of artificial intelligence (AI) into cancer vaccine development is revolutionizing the field by enhancing various aspect of design and delivery. This review explores how AI facilitates precise epitope design, optimizes mRNA and DNA vaccine instructions, and enables personalized vaccine strategies by predicting patient responses. By utilizing AI technologies, researchers can navigate complex biological datasets and uncover novel therapeutic targets, thereby improving the precision and efficacy of cancer vaccines. Despite the promise of AI-powered cancer vaccines, significant challenges remain, such as tumor heterogeneity and genetic variability, which can limit the effectiveness of neoantigen prediction. Moreover, ethical and regulatory concerns surrounding data privacy and algorithmic bias must be addressed to ensure responsible AI deployment. The future of cancer vaccine development lies in the seamless integration of AI to create personalized immunotherapies that offer targeted and effective cancer treatments. This review underscores the importance of interdisciplinary collaboration and innovation in overcoming these challenges and advancing cancer vaccine development. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeutic options. Due to a variety of cancer cell-intrinsic factors, including KRAS mutations, chemokine production, and other mechanisms that elicit a dysregulated host immune response, PDAC is often characterized by poor immune infiltration and an immune-privileged fibrotic stroma. As understanding of the tumor microenvironment (TME) evolves, novel therapies are being developed to target immunosuppressive mechanisms. Immune checkpoint inhibitors have limited efficacy when used alone or with radiation. Combinations of immune therapies, along with chemotherapy or chemoradiation, have demonstrated promise in preclinical and early clinical trials. Despite dismal response rates for immunotherapy for metastatic PDAC, response rates with neoadjuvant immunotherapy are somewhat encouraging, suggesting that incorporation of immunotherapy in the treatment of PDAC should be earlier in the disease course. Precision therapy for PDAC may be informed by advances in transcriptomic sequencing that can identify immunophenotypes, allowing for more appropriate treatment selection for each individual patient. Personalized and antigen-specific therapies are an increasing topic of interest, including adjuvant immunotherapy using personalized mRNA vaccines to prevent recurrence. Further development of personalized immune therapies will need to balance precision with generalizability and cost. [ABSTRACT FROM AUTHOR]

In immuno-oncology, the focus has traditionally been on αβ T cells, and immune checkpoint inhibitors that primarily target PD-1 or CTLA4 in these lymphocytes have revolutionized the management of multiple human malignancies. However, recent research highlights the crucial role of B cells and the antibodies they produce in antagonizing malignant progression, offering new avenues for immunotherapy. Our group has demonstrated that dimeric Immunoglobulin A can penetrate tumor cells, neutralize oncogenic drivers in endosomes, and expel them from the cytosol. This mechanistic insight suggests that engineered antibodies targeting this pathway may effectively reach previously inaccessible targets. Investigating antibody production within intratumoral germinal centers and understanding the impact of different immunoglobulins on malignant progression could furnish new tools for the therapeutic arsenal, including the development of tumor-penetrating antibodies. This review aims to elucidate the nature of humoral adaptive immune responses in human cancer and explore how they could herald a new era of immunotherapeutic modalities. By expanding the scope of antitumor immunotherapies, these approaches have the potential to benefit a broader range of cancer patients, particularly through the utilization of tumor cell–penetrating antibodies. [ABSTRACT FROM AUTHOR]

The malignant form of melanoma is one of the deadliest human cancers that accounts for almost all of the skin tumor-related fatalities in its later stages. Achieving an exhaustive understanding of reliable cancer-specific markers and molecular pathways can provide numerous practical techniques and direct the way toward the development of rational curative medicines to increase the lifespan of patients. Immunotherapy has significantly enhanced the treatment of metastatic and late-stage melanoma, resulting in an incredible increase in positive responses to therapy. Despite the increasing occurrence of melanoma, the median survival rate for patients with advanced, inoperable terminal disease has increased from around six months to almost six years. The current knowledge of the tumor microenvironment (TME) and its interaction with the immune system has resulted in the swift growth of innovative immunotherapy treatments. Exosomes are small extracellular vesicles (EVs), ranging from 30 to 150 nm in size, that the majority of cells released them. Exosomes possess natural advantages such as high compatibility with living organisms and low potential for causing immune reactions, making them practical for delivering therapeutic agents like chemotherapy drugs, nucleic acids, and proteins. This review highlights recent advancements in using exosomes as an approach to providing medications for the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Introduction: Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine. Methods: Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses. Results: MUC1 vaccine responders had higher frequencies of CD4 cells prevaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NFkB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy. Discussion: These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness. [ABSTRACT FROM AUTHOR]

A lot of hope for high‐risk cancers is being pinned on immunotherapy but the evidence in children is lacking due to the rarity and limited efficacy of single‐agent approaches. Here, we aim to assess the effectiveness of multimodal therapy comprising a personalized dendritic cell (DC) vaccine in children with relapsed and/or high‐risk solid tumors using the N‐of‐1 approach in real‐world scenario. A total of 160 evaluable events occurred in 48 patients during the 4‐year follow‐up. Overall survival of the cohort was 7.03 years. Disease control after vaccination was achieved in 53.8% patients. Comparative survival analysis showed the beneficial effect of DC vaccine beyond 2 years from initial diagnosis (HR = 0.53, P =.048) or in patients with disease control (HR = 0.16, P =.00053). A trend for synergistic effect with metronomic cyclophosphamide and/or vinblastine was indicated (HR = 0.60 P =.225). A strong synergistic effect was found for immune check‐point inhibitors (ICIs) after priming with the DC vaccine (HR = 0.40, P =.0047). In conclusion, the personalized DC vaccine was an effective component in the multimodal individualized treatment. Personalized DC vaccine was effective in less burdened or more indolent diseases with a favorable safety profile and synergized with metronomic and/or immunomodulating agents. [ABSTRACT FROM AUTHOR]

Recent breakthroughs in cancer immunotherapies have emphasized the importance of harnessing the immune system for treating cancer. Vaccines, which have traditionally been used to promote protective immunity against pathogens, are now being explored as a method to target cancer neoantigens. Over the past few years, extensive preclinical research and more than a hundred clinical trials have been dedicated to investigating various approaches to neoantigen discovery and vaccine formulations, encouraging development of personalized medicine. Nucleic acids (DNA and mRNA) have become particularly promising platform for the development of these cancer immunotherapies. This shift towards nucleic acid-based personalized vaccines has been facilitated by advancements in molecular techniques for identifying neoantigens, antigen prediction methodologies, and the development of new vaccine platforms. Generating these personalized vaccines involves a comprehensive pipeline that includes sequencing of patient tumor samples, data analysis for antigen prediction, and tailored vaccine manufacturing. In this review, we will discuss the various shared and personalized antigens used for cancer vaccine development and introduce strategies for identifying neoantigens through the characterization of gene mutation, transcription, translation and post translational modifications associated with oncogenesis. In addition, we will focus on the most up-to-date nucleic acid vaccine platforms, discuss the limitations of cancer vaccines as well as provide potential solutions, and raise key clinical and technical considerations in vaccine development. [ABSTRACT FROM AUTHOR]

Vaccines have been under development for over two centuries and have significantly contributed to the decline in infectious diseases and mortality rates by eliciting targeted immune responses against pathogens. Adjuvants, while typically non-immunogenic, play a vital role in modulating immune responses when combined with vaccines, reducing the necessary vaccine dosage and enhancing immune memory. Generally, vaccines are formulated with appropriate adjuvants to strengthen the immune response to the vaccine antigen and to assess their potential in preventing disease spread. Additionally, adjuvants are crucial in steering both humoral and cell-mediated immune responses to foster pathogenspecific immunity. There is an increasing emphasis on utilizing advanced technologies to develop novel vaccines aimed at problematic pathogens, particularly those that show limited efficacy with conventional vaccines and outdated production techniques. An ideal adjuvant should exhibit minimal to no adverse effects and ensure safety for both short-term and long-term applications. This article provides a concise overview of adjuvants, examining their significance in autoimmune diseases, especially concerning disease progression and related challenges. Acknowledging the growing skepticism surrounding vaccines in recent years is important, with some research supporting this perspective. Furthermore, we explore the function of adjuvants in cancer vaccines, categorized as therapeutic rather than preventive, noting the substantial advancements achieved in this area. [ABSTRACT FROM AUTHOR]

Vaccine‐based therapeutics for cancers face several challenges including lack of immunogenicity and tumor escape pathways for single antigen targets. It has been reported that radiotherapy has an in situ vaccine effect that provides tumor antigens following irradiation, helping to activate antigen‐presenting cells (APCs). Herein, a new vaccine approach is developed by combining genetically engineered irradiated tumor cell debris (RTD) and hyaluronic acid (HA), termed HA@RTD. A cancer cell line is developed that overexpresses granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). A hydrogel was developed by covalent conjugation of HA with RTD proteins that acted as a potent vaccine system, the effects which were probed with T cell receptor sequencing. The engineered vaccine activated antitumor immunity responses and prevented tumor growth in mice even with a single immunization. HA@RTD vaccine efficacy was also assessed in therapeutic settings with established tumors and in combination with immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

Despite treatment advances through immunotherapies, including anti-PD-1/PDL1 therapies, the overall prognosis of non-small cell lung cancer (NSCLC) patients remains poor, underscoring the need for novel approaches that offer long-term clinical benefit. This review examined the literature on the subject over the past 20 years to provide an update on the evolving landscape of dendritic cell-based immunotherapy to treat NSCLC, highlighting the crucial role of dendritic cells (DCs) in immune response initiation and regulation. These cells encompass heterogeneous subsets like cDC1s, cDC2s, and pDCs, capable of shaping antigen presentation and influencing T cell activation through the balance between the Th1, Th2, and Th17 profiles and the activation of regulatory T lymphocytes (Treg). The intricate interaction between DC subsets and the high density of intratumoral mature DCs shapes tumor-specific immune responses and impacts therapeutic outcomes. DC-based immunotherapy shows promise in overcoming immune resistance in NSCLC treatment. This article review provides an update on key clinical trial results, forming the basis for future studies to characterize the role of different types of DCs in situ and in combination with different therapies, including DC vaccines. [ABSTRACT FROM AUTHOR]

Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these intracranial tumors due to relatively low toxicity and tumor specificity. Here we show that SCIB1, a TRP-2 and gp100 directed ImmunoBody® DNA vaccine, generates a strong TRP-2 specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced and the detection of a significant number of pentamer positive T cells in the spleen of vaccinated mice. Furthermore, vaccine-induced T cells were able to recognize and kill B16HHDII/DR1 cells after a short in vitro culture. Having found that glioblastoma multiforme (GBM) expresses significant levels of PD-L1 and IDO1, with PD-L1 correlating with poorer survival in patients with the mesenchymal subtype of GBM, we decided to combine SCIB1 ImmunoBody® with PD-1 immune checkpoint blockade to treat mice harboring intracranial tumors expressing TRP-2 and gp100. Time-to-death was significantly prolonged, and this correlated with increased CD4+ and CD8+ T cell infiltration in the tissue microenvironment (TME). However, in addition to PD-L1 and IDO, the GBM TME was found to contain a significant number of immunoregulatory T (Treg) cell-associated transcripts, and the presence of such cells is likely to significantly affect clinical outcome unless also tackled. [ABSTRACT FROM AUTHOR]

Significant strides have been made in identifying tumour‐associated antigens over the past decade, revealing unique epitopes crucial for targeted cancer therapy. Among these, the New York esophageal squamous cell carcinoma (NY‐ESO‐1) protein, a cancer/testis antigen, stands out. This protein is presented on the cell surface by major histocompatibility complex class I molecules and exhibits restricted expression in germline cells and various cancers, marking it as an immune‐privileged site. Remarkably, NY‐ESO‐1 serves a dual role as both a tumour‐associated antigen and its own adjuvant, implying a potential function as a damage‐associated molecular pattern. It elicits strong humoural immune responses, with specific antibody frequencies significantly correlating with disease progression. These characteristics make NY‐ESO‐1 an appealing candidate for developing effective and specific immunotherapy, particularly for advanced stages of disease. In this review, we provide a comprehensive overview of NY‐ESO‐1 as an immunogenic tumour antigen. We then explore the diverse strategies for targeting NY‐ESO‐1, including cancer vaccination with peptides, proteins, DNA, mRNA, bacterial vectors, viral vectors, dendritic cells and artificial adjuvant vector cells, while considering the benefits and drawbacks of each strategy. Additionally, we offer an in‐depth analysis of adoptive T‐cell therapies, highlighting innovative techniques such as next‐generation NY‐ESO‐1 T‐cell products and the integration with lymph node‐targeted vaccines to address challenges and enhance therapeutic efficacy. Overall, this comprehensive review sheds light on the evolving landscape of NY‐ESO‐1 targeting and its potential implications for cancer treatment, opening avenues for future tailored directions in NY‐ESO‐1‐specific immunotherapy. Highlights: Endogenous immune response: NY‐ESO‐1 exhibited high immunogenicity, activating endogenous dendritic cells, T cells and B cells.NY‐ESO‐1‐based cancer vaccines: NY‐ESO‐1 vaccines using protein/peptide, RNA/DNA, microbial vectors and artificial adjuvant vector cells have shown promise in enhancing immune responses against tumours.NY‐ESO‐1‐specific T‐cell receptor‐engineered cells: NY‐ESO‐1‐targeted T cells, along with ongoing innovations in engineered natural killer cells and other cell therapies, have improved the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

mRNA delivery systems, such as lipid nanoparticle (LNP), have made remarkable strides in improving mRNA expression, whereas immune system activation operates on a threshold. Maintaining a delicate balance between antigen expression and dendritic cell (DC) activation is vital for effective immune recognition. Here, a water-in-oil-in-water (w/o/w) Pickering emulsion stabilized with calcium phosphate nanoparticles (CaP-PME) is developed for mRNA delivery in cancer vaccination. CaP-PME efficiently transports mRNA into the cytoplasm, induces pro-inflammatory responses and activates DCs by disrupting intracellular calcium/potassium ions balance. Unlike LNP, CaP-PME demonstrates a preference for DCs, enhancing their activation and migration to lymph nodes. It elicits interferon-γ-mediated CD8+ T cell responses and promotes NK cell proliferation and activation, leading to evident NK cells infiltration and ameliorated tumor microenvironment. The prepared w/o/w Pickering emulsion demonstrates superior anti-tumor effects in E.G7 and B16-OVA tumor models, offering promising prospects as an enhanced mRNA delivery vehicle for cancer vaccinations. [Display omitted] [ABSTRACT FROM AUTHOR]

Melanoma, known for its aggressive metastatic nature, presents a formidable challenge in cancer treatment, where conventional therapies often fall short. This study introduces a pioneering approach utilizing metal-free nanosystem as tumor vaccines, spotlighting their potential in revolutionizing melanoma treatment. This work employed organic nitroxides, specifically 4-carboxy-TEMPO, in combination with chitosan (CS), to create a novel nanocomposite material - the CS-TEMPO-OVA nanovaccines. This composition not only improves biocompatibility and extends blood circulation time of TEMPO but also marks a significant departure from traditional gadolinium-based contrast agents in MRI technology, addressing safety concerns. CS-TEMPO-OVA nanovaccines demonstrate excellent biocompatibility at both the cellular and organoid level. They effectively stimulate bone marrow-derived dendritic cells (BMDCs), which in turn promote the maturation and activation of T cells. This ultimately leads to a strong production of essential cytokines. These nanovaccines serve a dual purpose as both therapeutic and preventive. By inducing an immune response, activating cytotoxic T cells, and promoting macrophage M1 polarization, they effectively inhibit melanoma growth and enhance survival in mouse models. When combined with αPD-1, the CS-TEMPO-OVA nanovaccines significantly bolster the infiltration of cytotoxic T lymphocytes (CTLs) within tumors, sparking a powerful systemic antitumor response that effectively curbs tumor metastasis. The ability of these nanovaccines to control both primary (subcutaneous) and metastatic B16-OVA tumors highlights their remarkable efficacy. Furthermore, the CS-TEMPO-OVA nanovaccine can be administered in vivo via both intravenous and intramuscular routes, both of which effectively enhance the T 1 contrast of magnetic resonance imaging in tumor tissue. This study offers invaluable insights into the integrated application of these nanovaccines in both clinical diagnostics and treatment, marking a significant stride in cancer research and patient care. [Display omitted] [ABSTRACT FROM AUTHOR]