Development Of Cancer Vaccines Research Articles

Induced Pluripotent Stem Cells Facilitate the Development and Evaluation of Cancer Vaccines.

Cancer vaccines are an approach to elicit amplified antigen-specific immune responses. Induced pluripotent stem cells (iPSCs) have potential utility for the development of universal vaccines due to their intrinsic antigenic epitopes. Concurrently, iPSCs can undergo pluripotent differentiation and are thus a stable source of both antigen-presenting cells for producing immune cell-based vaccines and tumor organoids for facilitating the exploration and adaptive assessment of tumor vaccines. This review describes the specific contributions of iPSCs to vaccine development, summarizes their diverse developmental trajectories, and discusses the obstacles to their application along with potential solutions.

Prophylactic and therapeutic cancer vaccine with continuous localized immunomodulation

Selective in vivo immune cell manipulation offers a promising strategy for cancer vaccines. In this context, spatiotemporal control over recruitment of specific cells, and their direct exposure to appropriate immunoadjuvants and antigens are key to effective cancer vaccines. We present an implantable 3D-printed cancer vaccine platform called the ‘NanoLymph’ that enables spatiotemporally-controlled recruitment and manipulation of immune cells in a subcutaneous site. Leveraging two reservoirs each for continuous immunoadjuvant release or antigen presentation, the NanoLymph attracts dendritic cells (DCs) on site and exposes them to tumor-associated antigens. Upon local antigen-specific activation, DCs are mobilized to initiate a systemic immune response. NanoLymph releasing granulocyte-macrophage colony-stimulating factor and CpG-oligodeoxynucleotides with irradiated whole cell tumor lysate inhibited tumor growth of B16F10 murine melanoma in a prophylactic and therapeutic vaccine setting. Overall, this study presents the NanoLymph as a versatile cancer vaccine development platform with replenishable and controlled local release of antigens and immunoadjuvants.

MiRNA-Targeted Vaccines: A Promising Approach for Viral Attenuation and Immunogenicity Enhancement.

MicroRNAs (miRNAs) have emerged as a significant tool in the realm of vaccinology, offering novel approaches to vaccine development. This study investigates the potential of miRNAs in the development of advanced vaccines, with an emphasis on how they regulate immune response and control viral replication. We go over the molecular features of miRNAs, such as their capacity to direct post-transcriptional regulation toward mRNAs, hence regulating the expression of genes in diverse tissues and cells. This property is harnessed to develop live attenuated vaccines that are tissue-specific, enhancing safety and immunogenicity. The review highlights recent advancements in using miRNA-targeted vaccines against viruses like influenza, poliovirus, and tick-borne encephalitis virus, demonstrating their attenuated replication in specific tissues while retaining immunogenicity. We also explored the function of miRNAs in the biology of cancer, highlighting their potential to develop cancer vaccines through targeting miRNAs that are overexpressed in tumor cells. The difficulties in developing miRNA vaccines are also covered in this work, including delivery, stability, off-target effects, and the requirement for individualized cancer treatment plans. We wrap off by discussing the potential of miRNA vaccines and highlighting how they will influence the development of vaccination techniques for cancer and infectious diseases in the future.

Identification of a novel DEC-205 binding peptide to develop dendritic cell-targeting nanovaccine for cancer immunotherapy

Cancer vaccine is regarded as an effective immunotherapy approach mediated by dendritic cells (DCs) which are crucial for antigen presentation and the initiation of adaptive immune responses. However, lack of DC-targeting properties significantly hampers the efficacy of cancer vaccines. Here, by using the phage display technique, peptides targeting the endocytic receptor DEC-205 primarily found on cDC1s were initially screened. An optimized hydrolysis-resistant peptide, hr-8, was identified and conjugated to PLGA-loaded antigen (Ag) and CpG adjuvant nanoparticles, resulting in a DC-targeting nanovaccine. The nanovaccine hr-8-PLGA@Ag/CpG facilitates dendritic cell maturation and improves antigen cross-presentation. The nanovaccine can enhance the antitumor immune response mediated by CD8+ T cells by encapsulating the nanovaccine with either exogenous OVA protein antigen or endogenous gp100/E7 antigenic peptide. As a result, strong antitumor effects are observed in both anti-PD-1 responsive B16-OVA and anti-PD-1 non-responsive B16 and TC1 immunocompetent tumor models. In summary, this study presents the initial documentation of a nanovaccine that targets dendritic cells via the novel DEC-205 binding peptide. This approach offers a new method for developing cancer vaccines that can potentially improve the effectiveness of cancer immunotherapy.

S-Sulfenylation Driven Antigen Capture Boosted by Radiation for Enhanced Cancer Immunotherapy.

Radiotherapy (RT)-induced in situ vaccination greatly promotes the development of personalized cancer vaccines owing to the massive release of antigens initiated by tumor-localized RT eliciting the tumor-specific immune response. However, its broad application in cancer treatment is seriously impeded by poor antigen cross-presentation, low response rate, and short duration of efficacy. Herein, the tumor-antigen-capturing nanosystem dAuNPs@CpG consisting of gold nanoparticles, 3,5-cyclohexanedione (CHD), and immunoadjuvant CpG were fabricated to enhance RT-induced vaccination. Taking advantage of the specific covalent binding between CHD and sulfenic acids of antigen proteins, we show that this nanoplatform has an unexpected potential to capture the sulfenylated tumor-derived protein antigens (TDPAs) induced by RT to in situ generate a vaccination effect, achieving significant growth suppression of both primary and distant tumors in combination with PD-1 blockade. We thus believe that our work presents a powerful and effective means to improve the synergistic tumor radioimmunotherapy.

Development and Clinical Applications of Therapeutic Cancer Vaccines with Individualized and Shared Neoantigens.

Neoantigens, presented as peptides on the surfaces of cancer cells, have recently been proposed as optimal targets for immunotherapy in clinical practice. The promising outcomes of neoantigen-based cancer vaccines have inspired enthusiasm for their broader clinical applications. However, the individualized tumor-specific antigens (TSA) entail considerable costs and time due to the variable immunogenicity and response rates of these neoantigens-based vaccines, influenced by factors such as neoantigen response, vaccine types, and combination therapy. Given the crucial role of neoantigen efficacy, a number of bioinformatics algorithms and pipelines have been developed to improve the accuracy rate of prediction through considering a series of factors involving in HLA-peptide-TCR complex formation, including peptide presentation, HLA-peptide affinity, and TCR recognition. On the other hand, shared neoantigens, originating from driver mutations at hot mutation spots (e.g., KRASG12D), offer a promising and ideal target for the development of therapeutic cancer vaccines. A series of clinical practices have established the efficacy of these vaccines in patients with distinct HLA haplotypes. Moreover, increasing evidence demonstrated that a combination of tumor associated antigens (TAAs) and neoantigens can also improve the prognosis, thus expand the repertoire of shared neoantigens for cancer vaccines. In this review, we provide an overview of the complex process involved in identifying personalized neoantigens, their clinical applications, advances in vaccine technology, and explore the therapeutic potential of shared neoantigen strategies.

Picrasidine S Induces cGAS-Mediated Cellular Immune Response as a Novel Vaccine Adjuvant.

New adjuvants that trigger cellular immune responses are urgently needed for the effective development of cancer and virus vaccines. Motivated by recent discoveries that show activation of type I interferon (IFN-I) signaling boosts T cell immunity, this study proposes that targeting this pathway can be a strategic approach to identify novel vaccine adjuvants. Consequently, a comprehensive chemical screening of 6,800 small molecules is performed, which results in the discovery of the natural compound picrasidine S (PS) as an IFN-I inducer. Further analysis reveals that PS acts as a powerful adjuvant, significantly enhancing both humoral and cellular immune responses. At the molecular level, PS initiates the activation of the cGAS-IFN-I pathway, leading to an enhanced T cell response. PS vaccination notably increases the population of CD8+ central memory (TCM)-like cells and boosts the CD8+ T cell-mediated anti-tumor immune response. Thus, this study identifies PS as a promising candidate for developing vaccine adjuvants in cancer prevention.

Effect of NIR-II on cancer nanocomposite vaccines for lymph node targeted delivery and enhanced immunotherapy.

e20506 Background: Cancervaccines have become one of the hot areas of research in recent years. However, different types of tumors and the tumor tissue itself are heterogeneous. Some cancervaccines contain a single epitope and have weak immunogenicity. The antigen-presenting cells cannot adequately absorb and present the antigen peptide contained in the vaccine. As a result, the body fails to elicit an effective immune response, which greatly limits the therapeutic effect of the cancervaccine. In situ cancervaccines composed of antigens and adjuvants are a promising cancer treatment modality; however, convenient manufacturing of vaccines in vivo and their efficient delivery to lymph nodes (LNs) remain a significant challenge. In this study, we outline a facile approach to simultaneously achieve in situ programming of vaccines via two synergistic nanomedicines to generate robust immune responses. Methods: We first prepared two synergistic nanocomposite systems: Gold nanorods, amphiphilic polymer polyphosphate mPEG- b-PHEP encapsulating the immune adjuvant R848, and nanoparticles doped with cationic liposomes DOTAP. Two nanomedicines were characterized and the efficacy of the nanovaccine was verified at the Cellular Experiments. At the animal level, the lymph node targeting of the nanoparticles was demonstrated through IVIS. We also constructed distant model and lung metastasis model to verify the nanovaccine's effect on enhancing systemic immunotherapy. Results: We used amphiphilic polymer polyphosphate mPEG- b-PHEP to encapsulate TLR7/8 agonist R848 to obtain VNPR848 nanoparticles. Gold nanorods (~ 100nm) can produce a strong photothermal effect mediated by NIR-II, killing tumor cells and releasing abundant antigens at the same time. The small size of VNPR848 (~ 30nm) is beneficial to the enrichment of lymph nodes. After capturing the antigens produced by photothermal, nanoparticles will be targeted and delivered to the tumor draining lymph nodes together with R848, and will be effectively absorbed by DC cells. This in situ tumor vaccine with the ability of targeted delivery of lymph nodes can trigger a strong anti-tumor immune response. This therapy can completely inhibit distant tumors in some mice and produce a long-term immune memory effect on NSCLC metastasis. Conclusions: We propose a simple personalized in situ cancervaccine strategy, which uses nanotechnology to remove tumors in situ and release antigens. Antigens and immune adjuvants are simultaneously delivered to the draining lymph nodes to initiate the antigen presentation function of DC cells, resulting in an anti-tumor immune response to inhibit tumor recurrence and metastasis. The nano-vaccine based on powerful therapeutic effect provides an attractive technology for in situ programming of personalized cancervaccine and an effective strategy for the development of cancervaccine.

State-Of-The-Art Advancements on Cancer Vaccines and Biomarkers.

The origins of cancer vaccines date back to the 1800s. Since then, there have been significant efforts to generate vaccines against solid and hematologic malignancies using a variety of platforms. To date, these efforts have generally been met with minimal success. However, in the era of improved methods and technological advancements, supported by compelling preclinical and clinical data, a wave of renewed interest in the field offers the promise of discovering field-changing paradigms in the management of established and resected disease using cancer vaccines. These include novel approaches to personalized neoantigen vaccine development, as well as innovative immune-modulatory vaccines (IMVs) that facilitate activation of antiregulatory T cells to limit immunosuppression caused by regulatory immune cells. This article will introduce some of the limitations that have affected cancer vaccine development over the past several decades, followed by an introduction to the latest advancements in neoantigen vaccine and IMV therapy, and then conclude with a discussion of some of the newest technologies and progress that are occurring across the cancer vaccine space. Cancer vaccines are among the most promising frontiers for breakthrough innovations and strategies poised to make a measurable impact in the ongoing fight against cancer.

Immunotherapeutic Strategies Targeting Breast Cancer Stem Cells.

Breast cancer is the most commonly diagnosed cancer in women and is a leading cause of cancer death in women worldwide. Despite the implementation of multiple treatment options, including immunotherapy, breast cancer treatment remains a challenge. In this review, we aim to summarize present challenges in breast cancer immunotherapy and recent advancements in overcoming treatment resistance. We elaborate on the inhibition of signaling cascades, such as the Notch, Hedgehog, Hippo, and WNT signaling pathways, which regulate the self-renewal and differentiation of breast cancer stem cells and, consequently, disease progression and survival. Cancer stem cells represent a rare population of cancer cells, likely originating from non-malignant stem or progenitor cells, with the ability to evade immune surveillance and develop resistance to immunotherapeutic treatments. We also discuss the interactions between breast cancer stem cells and the immune system, including potential agents targeting breast cancer stem cell-associated signaling pathways, and provide an overview of the emerging approaches to breast cancer stem cell-targeted immunotherapy. Finally, we consider the development of breast cancer vaccines and adoptive cellular therapies, which train the immune system to recognize tumor-associated antigens, for eliciting T cell-mediated responses to target breast cancer stem cells.

Engineering W/O/W pickering emulsion for the enhanced antigen delivery and immune responses

Tumor immunotherapy, particularly cancer vaccines, holds promise for combating cancer by harnessing tailored immune responses against malignant cells. However, conventional approaches face challenges in efficiently delivering antigens for optimal immune activation. Emulsion adjuvants, like MF59, enhance cellular uptake but struggle to induce robust CD8+ T cell responses. Here, we introduce a novel strategy employing a water-in-oil-in-water (W/O/W) multiple Pickering emulsion (mPE) for antigen delivery. The mPE, utilizing biocompatible, pH-sensitive particles, encapsulates antigens within the inner water phase, ensuring enhanced intracellular processing and dictating the intracellular fate of antigens for improved cross-presentation. In vitro and in vivo studies demonstrated that mPEs induced robust dendritic cells activation and antigen cross-presentation, leading to a significantly enhanced immune response. Notably, calcium phosphate-stabilized mPE (CaP-mPE) illustrated the more robust IFN-γ+ T cell responses. In comparison with traditional surfactant-stabilized multiple emulsions, CaP-mPE significantly inhibit tumor growth and effectively prolong the survival of tumor-bearing mice. This innovative approach offers a promising avenue for the development of effective cancer vaccines with potent cellular immune responses.

Exosome-like Systems: From Therapies to Vaccination for Cancer Treatment and Prevention-Exploring the State of the Art.

Cancer remains one of the main causes of death in the world due to its increasing incidence and treatment difficulties. Although significant progress has been made in this field, innovative approaches are needed to reduce tumor incidence, progression, and spread. In particular, the development of cancer vaccines is currently ongoing as both a preventive and therapeutic strategy. This concept is not new, but few vaccines have been approved in oncology. Antigen-based vaccination emerges as a promising strategy, leveraging specific tumor antigens to activate the immune system response. However, challenges persist in finding suitable delivery systems and antigen preparation methods. Exosomes (EXs) are highly heterogeneous bilayer vesicles that carry several molecule types in the extracellular space. The peculiarity is that they may be released from different cells and may be able to induce direct or indirect stimulation of the immune system. In particular, EX-based vaccines may cause an anti-tumor immune attack or produce memory cells recognizing cancer antigens and inhibiting disease development. This review delves into EX composition, biogenesis, and immune-modulating properties, exploring their role as a tool for prevention and therapy in solid tumors. Finally, we describe future research directions to optimize vaccine efficacy and realize the full potential of EX-based cancer immunotherapy.

Application of Machine Learning Algorithms for Prediction of Tumor T-Cell Immunogens

The identification and characterization of immunogenic tumor antigens are essential for cancer vaccine development. In light of the impracticality of isolating and evaluating each putative antigen individually, in silico prediction algorithms, particularly those utilizing machine learning (ML) approaches, play a pivotal role. These algorithms significantly reduce the experimental workload necessary for discovering vaccine candidates. In this study, we employed six supervised ML methods on a dataset comprising 212 experimentally validated human tumor peptide antigens and an equal number of non-antigenic human peptides to develop models for immunogenicity prediction. These methods encompassed k-nearest neighbor (kNN), linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost). The models underwent validation through internal cross-validation within 10 groups from the training set and were further assessed using an external test set. Remarkably, the kNN model demonstrated superior performance, recognizing 90% of the known immunogens in the test set. The RF model excelled in the identification of non-immunogens, accurately classifying 93% of them in the test set. The three top-performing ML models according to multiple evaluation metrics (SVM, RF, and XGBoost) are to be subsequently integrated into the new version of the VaxiJen server, facilitating tumor antigen prediction through a majority voting mechanism.

Abstract PO4-16-05: Identification of functional HLA-A*11:01-restricted driver gene PIK3CA mutation specific T-cell receptors

Abstract The adoptive transfer of genetically engineered T-cell receptors (TCR-T) has emerged as a promising therapeutic strategy for the treatment of solid tumors. Recent clinical trials have demonstrated the safety and efficacy of TCR-T cell therapies against certain types of metastatic solid cancers. In our study, we aimed to investigate the potential of TCR-T cell therapies targeting neoantigens, which are exclusively expressed in cancer cells, with a focus on metastatic breast cancer (MBC). Specifically, we identified four driver missense mutations (PIK3CA E542K, E545K, H1047L, and H1047R) frequently observed in MBC patients and utilized computational tools to predict the generation of neoantigens. Utilizing NetMHCpan V.4.1, we performed screening of peptides spanning the mutation region and predicted a neoantigen epitope, PIK3CA_H1047L, to bind with HLA-A*11:01. To validate the presentation and stability of the neoantigen epitope, we employed TAP1-deficient K562 cells and observed stable expression of the mutant peptide-major histocompatibility complex (MHC) complex on the cell membrane. Subsequently, we isolated T cells from healthy donors possessing the HLA-A11:01 genotype, and subjected them to successive stimulations with neopeptide-pulsed dendritic cells. T cells stimulated with neopeptide were examined for neoantigen specificity using an IFN-γ ELISpot assay. Employing pMHC tetramer staining and single-cell sorting via flow cytometry, we successfully isolated five HLA-A11:01-restricted PIK3CA_H1047L-specific TCRs. Through lentivirus transduction of these TCRs into T cells, we achieved the generation of TCR-T cells that exhibited potent and specific activity exclusively against the PIK3CA_H1047L neoantigen. The functionality of the TCR-T cells was confirmed through assessments of CD137 expression, IFN-γ secretion, and cytotoxicity assays. In conclusion, our study demonstrates T cell responses towards neoantigens derived from PIK3CA, a commonly observed driver mutation in MBC. Furthermore, we successfully isolated five distinct neoantigen-specific TCRs that specifically recognized the PIK3CA_H1047L mutation and were restricted to the prevalent HLA-A*11:01 allele. The transfer of these TCRs into T cells resulted in the generation of TCR-T products exhibiting remarkable activity against the PIK3CA_H1047L neoantigen. These findings strongly encourage further investigation into TCRs targeting driver mutations in MBC, with the aim of advancing neoantigen-targeted TCR-T therapies into clinical trials. Additionally, the PIK3CA_H1047L neoantigen holds great promise as a potential candidate for the development of effective cancer vaccines. Citation Format: Meiying Shen, Xiaojian Han, Siyin Chen, Aishun Jin, Shengchun Liu. Identification of functional HLA-A*11:01-restricted driver gene PIK3CA mutation specific T-cell receptors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-16-05.

Focus on current and emerging treatment options for glioma: A comprehensive review.

This comprehensive review delves into the current updates and challenges associated with the management of low-grade gliomas (LGG), the predominant primary tumors in the central nervous system. With a general incidence rate of 5.81 per 100000, gliomas pose a significant global concern, necessitating advancements in treatment techniques to reduce mortality and morbidity. This review places a particular focus on immunotherapies, discussing promising agents such as Zotiraciclib and Lerapolturev. Zotiraciclib, a CDK9 inhibitor, has demonstrated efficacy in glioblastoma treatment in preclinical and clinical studies, showing its potential as a therapeutic breakthrough. Lerapolturev, a viral immunotherapy, induces inflammation in glioblastoma and displays positive outcomes in both adult and pediatric patients. Exploration of immunotherapy extends to Pembrolizumab, Nivolumab, and Entrectinib, revealing the challenges and variabilities in patient responses. Despite promising preclinical data, the monoclonal antibody Depatuxizumab has proven ineffective in glioblastoma treatment, emphasizing the critical need to understand resistance mechanisms. The review also covers the success of radiation therapy in pediatric LGG, with evolving techniques, such as proton therapy, showing potential improvements in patient quality of life. Surgical treatment is discussed in the context of achieving a balance between preserving the patient's quality of life and attaining gross total resection, with the extent of surgical resection significantly influencing the survival outcomes. In addition to advancements in cancer vaccine development, this review highlights the evolving landscape of LGG treatment, emphasizing a shift toward personalized and targeted therapies. Ongoing research is essential for refining strategies and enhancing outcomes in the management of LGG.

Progress in the development of vaccines for pancreatic adenocarcinoma

Pancreatic cancer, which is regarded as the third deadliest cancer globally, poses a significant challenge because of its limited range of treatment options and high mortality rate. Currently, there is a focus on both the development of a novel concept in vaccine designing and the parallel study of the associated immune mechanisms. To further our understanding of the healthcare field, a variety of promising designs have been introduced for in-depth study. The designs were developed to include the mKRAS-specific amphiphile vaccine, which targets a specific mutation in the KRAS gene in addition to the multi-antigen targeted DNA vaccine, which aims to stimulate an immune response against multiple cancer antigens. Furthermore, later designs of vaccines were introduced based on the development of peptide-based cancer vaccines, mRNA-based vaccines, cell-based vaccines, and engineered bacterial vectors using an oral Salmonella-based vaccine. The study presents the concept on which the new vaccine is based and discusses the up-to-date immunological manifestations of these designed vaccines.

Abstract CT108: Phase I data from TENDU101, a first-in-human trial of a novel synthetic peptide conjugate cancer vaccine platform assessed in recurrent prostate cancer patients before salvage treatment

Abstract Synthetic peptides are explored in the clinic in cancer vaccine development for the purpose of inducing tumor-directed T cell responses. Their immunogenicity is dependent on the chosen adjuvant and target organ exposure (lymphoid organs). To improve peptide immunogenicity, we have developed a technology enabling cross-linking of endogenous, pre-existing circulating antibodies (Abs) by employing a three-dimensional chemistry design. Multiple identical tetanus toxin-derived B cell epitopes (MTTEs) are conjugated to synthetically made antigenic tumor peptides intended to induce T cell responses. Here we report the first clinical safety assessment of the vaccine platform in the trial TENDU101 (NCT04701021). The cancer vaccine candidate (TENDU) was designed to include longer synthetic peptides harboring prostate cancer derived epitopes (CD4 and CD8) from PAP and PSMA. The study was a 3+3 design and doses were 40, 400 and 960 microgram in patients with documented recurrent disease after radical prostatectomy. A tetanus toxoid (TTd) containing vaccine boost was followed by TENDU vaccination via subcutaneous injection in the abdomen (4 doses in total with a 2 week interval) in n=9 patients (gr 1, 2, 3.1). For group 3.2 (n=3) TENDU vaccination was administrated in the same arm as the TTd vaccination. Primary objective was safety and secondary objective assessment of immune responses and preliminary anti-tumor responses. A total of 52 adverse events (AEs) were reported, most mild and deemed unrelated to vaccination. Six treatment-related AEs were reported of which 50% were mild transient injection site reactions in a single patient (gr 3.1), and three events of increases in lipase levels in two patients (gr 2). No serious AEs was reported. T cell responses pre/post TENDU were assessed in a total of six patients of which five patients displayed increased response against vaccine-related CD8 and CD4 epitopes (ELISpot). The three patients with the greatest increase in T cell responses were found to display the highest anti-MTTE IgG responses. A trend towards decrease in circulating tumor cells from screening to the end of treatment visit was observed in the patients with the highest levels of anti-MTTE IgGs post TENDU vaccination. There were no trends for decrease in PSA and/or PAP at the end of treatment and follow-up measurements were affected by initiation of radiation and short-term androgen deprivation. The administration of TTd and TENDU to the same anatomical location although spaced in time appeared to negatively influence immune responses to TTd and TENDU. In conclusion, the novel synthetic peptide conjugate vaccine conjugate was found safe with no serious AEs reported and a positive correlation between anti-MTTE and T cell responses was noted in patients when TENDU was administrated in the abdomen. Citation Format: Wolfgang Lilleby, Anna Bergqvist, Aikaterini Nasi, Wenche Rasch, Sara Mangsbo. Phase I data from TENDU101, a first-in-human trial of a novel synthetic peptide conjugate cancer vaccine platform assessed in recurrent prostate cancer patients before salvage treatment [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 CT108.

Abstract NG01: Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity

Abstract NG01: Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity

WT1 Cancer Vaccine in Advanced Pancreatic Cancer: A Systematic Review.

Advanced pancreatic cancer is one of the prominent contributors to cancer-related mortality globally. Chemotherapy, especially gemcitabine, is generally used for the treatment of advanced pancreatic cancer. Despite the treatment, the fatality rate for advanced pancreatic cancer is alarmingly high. Thus, the dire need for better treatment alternatives has drawn focus to cancer vaccinations. The Wilms tumor gene (WT1), typically associated with Wilms tumor, is found to be excessively expressed in some cancers, such as pancreatic cancer. This characteristic feature is harvested to develop cancer vaccines against WT1. This review aims to systematically summarize the clinical trials investigating the efficacy and safety of WT1 vaccines in patients with advanced pancreatic cancer. An extensive literature search was conducted on databases Medline, Web of Science, ScienceDirect, and Google Scholar using the keywords "Advanced pancreatic cancer," "Cancer vaccines," "WT1 vaccines," and "Pulsed DC vaccines," and the results were exclusively studied to construct this review. WT1 vaccines work by introducing peptides from the WT1 protein to trigger an immune response involving cytotoxic T lymphocytes via antigen-presenting cells. Upon activation, these lymphocytes induce apoptosis in cancer cells by specifically targeting those with increased WT1 levels. WT1 vaccinations, which are usually given in addition to chemotherapy, have demonstrated clinically positive results and minimal side effects. However, there are several challenges to their widespread use, such as the immunosuppressive nature of tumors and heterogeneity in expression. Despite these limitations, the risk-benefit profile of cancer vaccines is encouraging, especially for the WT1 vaccine in the treatment of advanced pancreatic cancer. Considering the fledgling status of their development, large multicentric, variables-matched, extensive analysis across diverse demographics is considered essential.

Immune Specific and Tumor-Dependent mRNA Vaccines for Cancer Immunotherapy: Reprogramming Clinical Translation into Tumor Editing Therapy.

Extensive research into mRNA vaccines for cancer therapy in preclinical and clinical trials has prepared the ground for the quick development of immune-specific mRNA vaccines during the COVID-19 pandemic. Therapeutic cancer vaccines based on mRNA are well tolerated, and are an attractive choice for future cancer immunotherapy. Ideal personalized tumor-dependent mRNA vaccines could stimulate both humoral and cellular immunity by overcoming cancer-induced immune suppression and tumor relapse. The stability, structure, and distribution strategies of mRNA-based vaccines have been improved by technological innovations, and patients with diverse tumor types are now being enrolled in numerous clinical trials investigating mRNA vaccine therapy. Despite the fact that therapeutic mRNA-based cancer vaccines have not yet received clinical approval, early clinical trials with mRNA vaccines as monotherapy and in conjunction with checkpoint inhibitors have shown promising results. In this review, we analyze the most recent clinical developments in mRNA-based cancer vaccines and discuss the optimal platforms for the creation of mRNA vaccines. We also discuss the development of the cancer vaccines' clinical research, paying particular attention to their clinical use and therapeutic efficacy, which could facilitate the design of mRNA-based vaccines in the near future.