RESUMO
Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.
Assuntos
Vacinas Anticâncer , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Gencitabina , Imunoterapia , Nanopartículas , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/farmacologia , Animais , Imunoterapia/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Nanopartículas/química , Camundongos , Humanos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Feminino , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , NanovacinasRESUMO
Memory T cells play a key role in immune protection against cancer. Vaccine-induced tissue-resident memory T (TRM) cells in the lung have been shown to protect against lung metastasis. Identifying the source of lung TRM cells can help to improve strategies, preventing tumor metastasis. Here, we found that a prime-boost vaccination approach using intramuscular DNA vaccine priming, followed by intranasal live-attenuated influenza-vectored vaccine (LAIV) boosting induced higher frequencies of lung CD8+ TRM cells compared with other vaccination regimens. Vaccine-induced lung CD8+ TRM cells, but not circulating memory T cells, conferred significant protection against metastatic melanoma and mesothelioma. Central memory T (TCM) cells induced by the DNA vaccination were major precursors of lung TRM cells established after the intranasal LAIV boost. Single-cell RNA sequencing analysis indicated that transcriptional reprogramming of TCM cells for differentiation into TRM cells in the lungs started as early as day 2 post the LAIV boost. Intranasal LAIV altered the mucosal microenvironment to recruit TCM cells via CXCR3-dependent chemotaxis and induced CD8+ TRM-associated transcriptional programs. These results identified TCM cells as the source of vaccine-induced CD8+ TRM cells that protect against lung metastasis. Significance: Prime-boost vaccination shapes the mucosal microenvironment and reprograms central memory T cells to generate lung resident memory T cells that protect against lung metastasis, providing insights for the optimization of vaccine strategies.
Assuntos
Linfócitos T CD8-Positivos , Vacinas Anticâncer , Memória Imunológica , Neoplasias Pulmonares , Células T de Memória , Animais , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Camundongos , Células T de Memória/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Camundongos Endogâmicos C57BL , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Imunização Secundária/métodos , Vacinação/métodos , Feminino , Humanos , Administração Intranasal , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Pulmão/imunologia , Pulmão/patologiaRESUMO
Neoantigen vaccines represent an emerging and promising strategy in the field of tumor immunotherapy. Despite their potential, designing an effective neoantigen vaccine remains a challenge due to the current limitations in predicting CD4+ T cell epitopes with high accuracy. Here, we introduce a novel approach to neoantigen vaccine design that does not rely on computational prediction of CD4+ T cell epitopes. Utilizing nitrated helper T cell epitope containing p-nitrophenylalanine, termed "NitraTh epitope," we have successfully engineered a series of tumor neoantigen vaccines capable of eliciting robust neoantigen-specific immune responses. With the help of NitraTh epitope, even mutations with low predicted affinity for MHC class I molecules were successfully induced to elicit neoantigen-specific responses. In H22 cell allograft and patient-derived xenograft (PDX) liver cancer mouse models, the NitraTh epitope-based neoantigen vaccines significantly suppressed tumor progression. More strikingly, through single-cell sequencing we found that the NitraTh epitope-based neoantigen vaccines regulate macrophage reprogramming and modulate macrophages to decrease the levels of the immunosuppressive molecule prostaglandin E2 (PGE2), which in turn reshapes the tumor immunosuppressive microenvironment. In summary, NitraTh epitope-based neoantigen vaccines possess the dual effects of potently activating neoantigen-specific immunity and alleviating immunosuppression, potentially providing a new paradigm for the design of tumor neoantigen vaccines.
Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Imunoterapia , Vacinas Anticâncer/imunologia , Animais , Camundongos , Humanos , Imunoterapia/métodos , Antígenos de Neoplasias/imunologia , Epitopos de Linfócito T/imunologia , Microambiente Tumoral/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Neoplasias/imunologia , Neoplasias/terapia , Ensaios Antitumorais Modelo de Xenoenxerto , FemininoRESUMO
BACKGROUND: Tumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor. METHODS: The validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model. RESULTS: EP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4+ Th1 cells supplemented by ACT and antigen-specific CD8+ T cells elicited by the EP-mediated DNA vaccination. CONCLUSIONS: Our preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes.
Assuntos
Vacinas Anticâncer , Eletroporação , Vacinas de DNA , Animais , Vacinas de DNA/imunologia , Eletroporação/métodos , Camundongos , Vacinas Anticâncer/imunologia , Camundongos Endogâmicos C57BL , Imunoterapia Adotiva/métodos , Feminino , Humanos , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Modelos Animais de Doenças , Linhagem Celular Tumoral , Células Alógenas/imunologia , Receptores ErbB/imunologiaRESUMO
Homologous animal cell product was obtained in protocol developed for female BALB/c mice. Dendritic cell (DC) migration from the injection site into the draining lymph nodes was evaluated. The number of DC labeled with carboxyfluorescein succinimidyl ester (CFSE) in draining lymph nodes increased from 5.3% (16 h) to 13.3% (48 h) (p=0.028) with a maximum at 72 h (15.4%, p=0.003). The immunophenotype of CFSE-DC detected in murine lymph nodes corresponded to the immunophenotype of mature vaccine DCs: they expressed differentiation markers CD11c, CD80, CD83, and CD86 (p>0.05 vs initial DC).
Assuntos
Vacinas Anticâncer , Células Dendríticas , Linfonodos , Camundongos Endogâmicos BALB C , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Vacinas Anticâncer/imunologia , Camundongos , Linfonodos/imunologia , Linfonodos/metabolismo , Succinimidas , Antígenos CD/imunologia , Antígenos CD/metabolismo , Fluoresceínas , Antígeno CD11c/metabolismo , Antígeno CD11c/imunologia , Antígeno B7-2/metabolismo , Antígeno B7-2/imunologia , Antígeno B7-1/metabolismo , Antígeno B7-1/imunologia , Antígeno CD83 , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Imunoglobulinas/imunologia , Imunoglobulinas/metabolismo , Diferenciação Celular , Distribuição Tecidual , Imunofenotipagem , Movimento CelularRESUMO
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.
Assuntos
Antígenos de Neoplasias , Imunoterapia , Proteínas de Membrana , Neoplasias , Humanos , Antígenos de Neoplasias/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Neoplasias/imunologia , Proteínas de Membrana/imunologia , Proteínas de Membrana/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/imunologiaRESUMO
The advent of RNA therapy, particularly through the development of mRNA cancer vaccines, has ushered in a new era in the field of oncology. This article provides a concise overview of the key principles, recent advancements, and potential implications of mRNA cancer vaccines as a groundbreaking modality in cancer treatment. mRNA cancer vaccines represent a revolutionary approach to combatting cancer by leveraging the body's innate immune system. These vaccines are designed to deliver specific mRNA sequences encoding cancer-associated antigens, prompting the immune system to recognize and mount a targeted response against malignant cells. This personalized and adaptive nature of mRNA vaccines holds immense potential for addressing the heterogeneity of cancer and tailoring treatments to individual patients. Recent breakthroughs in the development of mRNA vaccines, exemplified by the success of COVID-19 vaccines, have accelerated their application in oncology. The mRNA platform's versatility allows for the rapid adaptation of vaccine candidates to various cancer types, presenting an agile and promising avenue for therapeutic intervention. Clinical trials of mRNA cancer vaccines have demonstrated encouraging results in terms of safety, immunogenicity, and efficacy. Pioneering candidates, such as BioNTech's BNT111 and Moderna's mRNA-4157, have exhibited promising outcomes in targeting melanoma and solid tumors, respectively. These successes underscore the potential of mRNA vaccines to elicit robust and durable anti-cancer immune responses. While the field holds great promise, challenges such as manufacturing complexities and cost considerations need to be addressed for widespread adoption. The development of scalable and cost-effective manufacturing processes, along with ongoing clinical research, will be pivotal in realizing the full potential of mRNA cancer vaccines. Overall, mRNA cancer vaccines represent a cutting-edge therapeutic approach that holds the promise of transforming cancer treatment. As research progresses, addressing challenges and refining manufacturing processes will be crucial in advancing these vaccines from clinical trials to mainstream oncology practice, offering new hope for patients in the fight against cancer.
Assuntos
Vacinas Anticâncer , Neoplasias , Desenvolvimento de Vacinas , Vacinas de mRNA , Humanos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/prevenção & controle , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/imunologia , Vacinas Sintéticas/imunologia , RNA Mensageiro/genética , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , SARS-CoV-2/imunologia , SARS-CoV-2/genéticaRESUMO
The increasing interest in bacteriophage technology has prompted its novel applications to treat different medical conditions, most interestingly cancer. Due to their high specificity, manipulability, nontoxicity, and nanosize nature, phages are promising carriers in targeted therapy and cancer immunotherapy. This approach is particularly timely, as current challenges in cancer research include damage to healthy cells, inefficiency in targeting, obstruction by biological barriers, and drug resistance. Some cancers are being kept at the forefront of phage research, such as colorectal cancer and HCC, while others like lymphoma, cervical cancer, and myeloma have not been retouched in a decade. Common mechanisms are immunogenic antigen display on phage coats and the use of phage as transporters to carry drugs, genes, and other molecules. To date, popular phage treatments being tested are gene therapy and phage-based vaccines using M13 and λ phage, with some vaccines having advanced to human clinical trials. The results from most of these studies have been promising, but limitations in phage-based therapies such as reticuloendothelial system clearance or diffusion inefficiency must be addressed. Before phage-based therapies for cancer can be successfully used in oncology practice, more in-depth research and support from local governments are required.
Assuntos
Neoplasias , Terapia por Fagos , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Terapia por Fagos/métodos , Bacteriófagos/fisiologia , Imunoterapia/métodos , Animais , Terapia Genética/métodos , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/imunologiaRESUMO
Subunit vaccines have emerged as a promising strategy in immunotherapy for combating viral infections and cancer. Nevertheless, the clinical application of subunit vaccines is hindered by limitations in antigen delivery efficiency, characterized by rapid clearance and inadequate cellular uptake. Here, a novel subunit vaccine delivery system utilizing ovalbumin@magnetic nanoparticles (OVA@MNPs) encapsulated within biodegradable gelatin methacryloyl (GelMA) microspheres was proposed to enhance the efficacy of antigen delivery. OVA@MNPs-loaded GelMA microspheres, denoted as OMGMs, can be navigated through magnetic fields to deliver subunit vaccines into the lymphatic system efficiently. Moreover, the biodegradable OMGMs enabled the sustained release of subunit vaccines, concentrating OVA around lymph nodes and enhancing the efficacy of induced immune response. OMGMs were produced through a microfluidic droplet generation technique, enabling mass production. In murine models, OMGMs successfully accumulated antigens in lymph nodes abundant in antigen-presenting cells, leading to enhanced cellular and humoral immunity and pronounced antitumor effects with a single booster immunization. In conclusion, these findings highlight the promise of OMGMs as a practical subunit vaccination approach, thus addressing the limitations associated with antigen delivery efficiency and paving the way for advanced immunotherapeutic strategies.
Assuntos
Imunoterapia , Microesferas , Ovalbumina , Vacinas de Subunidades Antigênicas , Animais , Camundongos , Ovalbumina/química , Ovalbumina/imunologia , Ovalbumina/administração & dosagem , Vacinas de Subunidades Antigênicas/química , Vacinas de Subunidades Antigênicas/imunologia , Nanopartículas de Magnetita/química , Camundongos Endogâmicos C57BL , Feminino , Gelatina/química , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Sistemas de Liberação de Medicamentos/métodosRESUMO
ABSTRACT: The immune revolution that swept the field of oncology in the mid-2010s with the advent of checkpoint inhibitors has led to a paradigm shift in approaches toward adapting new cancer prevention modalities. Cancer vaccines have emerged from this era with astounding potential as a durable intervention to prevent cancers especially for patients with hereditary susceptibilities such as Lynch syndrome carriers. This review covers new insights in the immunoprevention landscape for patients living with Lynch syndrome including highlights ranging from clinical trials exploring the use of chemoprevention agents to boost immune cellularity to investigative studies using novel vaccine approaches to induce long-term antitumor immunity.
Assuntos
Vacinas Anticâncer , Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/imunologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Quimioprevenção/métodos , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais/etiologiaRESUMO
Cancer immunotherapy represents a promising targeted treatment by leveraging the patient's immune system or adoptive transfer of active immune cells to selectively eliminate cancer cells. Despite notable clinical successes, conventional immunotherapies face significant challenges stemming from the poor infiltration of endogenous or adoptively transferred cytotoxic T cells in tumors, immunosuppressive tumor microenvironment and the immune evasion capability of cancer cells, leading to limited efficacy in many types of solid tumors. Overcoming these hurdles is essential to broaden the applicability of immunotherapies. Recent advances in nanotherapeutics have emerged as an innovative tool to overcome these challenges and enhance the therapeutic potential of tumor immunotherapy. The unique biochemical and biophysical properties of nanomaterials offer advantages in activation of immune cells in vitro for cell therapy, targeted delivery, and controlled release of immunomodulatory agents in vivo. Nanoparticles are excellent carriers for tumor associated antigens or neoantigen peptides for tumor vaccine, empowering activation of tumor specific T cell responses. By precisely delivering immunomodulatory agents to the tumor site, immunoactivating nanoparticles can promote tumor infiltration of endogenous T cells or adoptively transferred T cells into tumors, to overcoming delivery and biological barriers in the tumor microenvironment, augmenting the immune system's ability to recognize and eliminate cancer cells. This review provides an overview of the current advances in immunotherapeutic approaches utilizing nanotechnology. With a focus on discussions concerning strategies to enhance activity and efficacy of cytotoxic T cells and explore the intersection of engineering nanoparticles and immunomodulation aimed at bolstering T cell-mediated immune responses, we introduce various nanoparticle formulations designed to deliver therapeutic payloads, tumor antigens and immunomodulatory agents for T cell activation. Diverse mechanisms through which nanoparticle-based approaches influence T cell responses by improving antigen presentation, promoting immune cell trafficking, and reprogramming immunosuppressive tumor microenvironments to potentiate anti-tumor immunity are examined. Additionally, the synergistic potential of combining nanotherapeutics with existing immunotherapies, such as immune checkpoint inhibitors and adoptive T cell therapies is explored. In conclusion, this review highlights emerging research advances on activation of cytotoxic T cells using nanoparticle agents to support the promises and potential applications of nanoparticle-based immunomodulatory agents for cancer immunotherapy.
Assuntos
Imunoterapia , Nanopartículas , Neoplasias , Linfócitos T Citotóxicos , Microambiente Tumoral , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Animais , Agentes de Imunomodulação/química , Agentes de Imunomodulação/farmacologia , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologiaRESUMO
Tumor neoantigens possess specific immunogenicity and personalized therapeutic vaccines based on neoantigens which have shown promising results in some clinical trials, with broad application prospects. However, the field is developing rapidly and there are currently few relevant review articles. Summarizing and analyzing the status of global personalized neoantigen vaccine clinical trials will provide important data for all stakeholders in drug development. Based on the Trialtrove database, a retrospective analysis was conducted using trial quantity as a key indicator for neo-adjuvant and adjuvant therapy anti-PD-1/PD-L1 clinical trials initiated before the end of 2022. The time trend of newly initiated trials was investigated. The sponsor type, host country, treatment mode, combination strategy, tested drugs, and targeted cancer types of these trials were summarized. As of December 2022, a total of 199 trials were included in the analysis. Among these studies, Phase I studies were the most numerous (119, 59.8%), and Phase I studies have been the predominant study type since 2015. Peptide vaccines were the largest neoantigen vaccines type, accounting for 64.8% of all clinical trials. Based on peptide delivery platforms, the proportion of trials was highest for the DC system (32, 16.1%), followed by LNP (11, 5.5%), LPX (11, 5.5%), and viruses (7, 3.5%). Most vaccines were applied in trials as a monotherapy (133/199, 66.8%), meanwhile combining immunotherapeutic drugs was the most common form for combination therapy. In terms of indications, the largest number of trials involved three or more unspecified solid tumors (50/199, 25.1%), followed by non-small cell lung cancer (24/199, 12.1%) and pancreatic cancer (15/199, 7.5%). The clinical development of personalized neoantigen cancer vaccines is still in the early stage. A clear shift in delivery systems from peptides to DC and liposomal platforms, with the largest number of studies in Asia, collectively marks a new era in the field. The adjuvant or maintenance therapy, and the combination treatment with ICIs are becoming the important clinical development orientation. As research on tumor-immune interactions intensifies, the design, development, and application of neoantigen vaccines are bound to develop rapidly, which will bring a new revolution in the future cancer treatment.
Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Neoplasias , Medicina de Precisão , Humanos , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/imunologia , Antígenos de Neoplasias/imunologia , Medicina de Precisão/métodos , Neoplasias/terapia , Neoplasias/imunologia , Ensaios Clínicos como Assunto , Estudos Retrospectivos , Imunoterapia/métodosRESUMO
Pancreatic adenocarcinoma (PDA) represents the fourth leading cause of cancer-related mortality in the USA. Only 20% of patients present surgically resectable and potentially curable tumors at diagnosis, while 80% are destined for poor survival and palliative chemotherapy. Accordingly, the advancement of innovative and effective therapeutic strategies represents a pivotal medical imperative. It has been demonstrated that targeting the immune system represents an effective approach against several solid tumors. The immunotherapy approach encompasses a range of strategies, including the administration of antibodies targeting checkpoint molecules (immune checkpoint inhibitors, ICIs) to disrupt tumor suppression mechanisms and active immunization approaches that aim to stimulate the host's immune system. While vaccines have proved effective against infectious agents, vaccines for cancer remain an unfulfilled promise. Vaccine-based therapy targeting tumor antigens has the potential to be a highly effective strategy for initiating and maintaining T cell recognition, enhancing the immune response, and ultimately promoting cancer treatment success. In this review, we examined the most recent clinical trials that employed diverse vaccine types to stimulate PDA patients' immune systems, either independently or in combination with chemotherapy, radiotherapy, ICIs, and monoclonal antibodies with the aim of ameliorating PDA patients' quality of life and extend their survival.
Assuntos
Vacinas Anticâncer , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Animais , Ensaios Clínicos como Assunto , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
Circular RNAs (circRNAs) are a novel class of noncoding RNAs that have emerged as pivotal players in gene regulation. Our understanding of circRNAs has greatly expanded over the last decade, with studies elucidating their biology and exploring their therapeutic applications. In this review, we provide an overview of the current understanding of circRNA biogenesis, outline their mechanisms of action in cancer, and assess their clinical potential as biomarkers. Furthermore, we discuss circRNAs as a potential therapeutic strategy, including recent advances in circRNA production and translation, along with proof-of-concept preclinical studies of cancer vaccines.
Assuntos
Biomarcadores Tumorais , Neoplasias , RNA Circular , RNA Circular/genética , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Biomarcadores Tumorais/genética , Animais , Regulação Neoplásica da Expressão Gênica , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologiaRESUMO
Cancer vaccine development is inhibited by a lack of strategies for directing dendritic cell (DC) induction of effective tumor-specific cellular immunity. Pathogen engagement of DC lectins and toll-like receptors (TLRs) is thought to shape immunity by directing T cell function. Controlling downstream responses, however, remains a major challenge. A critical goal in advancing vaccine development involves the identification of receptors that drive type 1 cellular immunity. The immune system monitors cells for aberrant glycosylation (a sign of a foreign entity), but potent activation occurs when a second signal, such as single-stranded RNA or lipopolysaccharide, is present to activate TLR signaling. To exploit dual signaling, we engineered a glycan-costumed virus-like particle (VLP) vaccine that displays a DC-SIGN-selective aryl mannose ligand and encapsulates TLR7 agonists. These VLPs deliver programmable peptide antigens to induce robust DC activation and type 1 cellular immunity. In contrast, VLPs lacking this critical DC-SIGN ligand promoted DC-mediated humoral immunity, offering limited tumor control. Vaccination with glycan-costumed VLPs generated tumor antigen-specific Th1 CD4+ and CD8+ T cells that infiltrated solid tumors, significantly inhibiting tumor growth in a murine melanoma model. The tailored VLPs also afforded protection against the reintroduction of tumor cells. Thus, DC lectin-driven immune reprogramming, combined with the modular programmability of VLP platforms, provides a promising framework for directing cellular immunity to advance cancer immunotherapies and vaccines.
Assuntos
Vacinas Anticâncer , Células Dendríticas , Lectinas Tipo C , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Animais , Camundongos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/química , Lectinas Tipo C/metabolismo , Lectinas Tipo C/imunologia , Camundongos Endogâmicos C57BL , Humanos , Vacinas de Partículas Semelhantes a Vírus/química , Vacinas de Partículas Semelhantes a Vírus/imunologia , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Carboidratos/química , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/imunologia , Polissacarídeos/química , Imunidade CelularRESUMO
Tumor neoantigen peptide vaccines hold potential for boosting cancer immunotherapy, yet efficiently co-delivering peptides and adjuvants to antigen-presenting cells in vivo remains challenging. Virus-like particle (VLP), which is a kind of multiprotein structure organized as virus, can deliver therapeutic substances into cells and stimulate immune response. However, the weak targeted delivery of VLP in vivo and its susceptibility to neutralization by antibodies hinder their clinical applications. Here, we first designed a novel protein carrier using the mammalian-derived capsid protein PEG10, which can self-assemble into endogenous VLP (eVLP) with high protein loading and transfection efficiency. Then, an engineered tumor vaccine, named ePAC, was developed by packaging genetically encoded neoantigen into eVLP with further modification of CpG-ODN on its surface to serve as an adjuvant and targeting unit to dendritic cells (DCs). Significantly, ePAC can efficiently target and transport neoantigens to DCs, and promote DCs maturation to induce neoantigen-specific T cells. Moreover, in mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy. Overall, these results support that ePAC could be safely utilized as cancer vaccines for antitumor therapy, showing significant potential for clinical translation.
Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Células Dendríticas , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/administração & dosagem , Camundongos , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Humanos , Células Dendríticas/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/genética , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Peptídeos/imunologia , Feminino , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , VacinaçãoRESUMO
Inducing high levels of antigen-specific CD8α+ T cells in the tumor is beneficial for cancer immunotherapy, but achieving this in a safe and effective manner remains challenging. Here, we have developed a designer liposomal nanovaccine containing a sonosensitizer (LNVS) to efficiently program T cell immunity in mice. Following intravenous injection, LNVS accumulates in the spleen in a protein corona and fluidity-dependent manner, leading to greater frequencies of antigen-specific CD8α+ T cells than soluble vaccines (the mixture of antigens and adjuvants). Meanwhile, some LNVS passively accumulates in the tumor, where it responds to ultrasound (US) to increase the levels of chemokines and adhesion molecules that are beneficial for recruiting CD8α+ T cells to the tumor. LNVS + US induces higher levels of intratumoral antitumor T cells than traditional sonodynamic therapy, regresses established mouse MC38 tumors and orthotopic cervical cancer, and protects cured mice from relapse. Our platform sheds light on the importance of tuning the fluidity and protein corona of naovaccines to program T cell immunity in mice and may inspire new strategies for cancer immunotherapy.
Assuntos
Linfócitos T CD8-Positivos , Vacinas Anticâncer , Imunoterapia , Lipossomos , Camundongos Endogâmicos C57BL , Animais , Lipossomos/química , Camundongos , Feminino , Imunoterapia/métodos , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral , Nanopartículas/química , Neoplasias/imunologia , Neoplasias/terapia , Humanos , NanovacinasRESUMO
Background: Tumor vaccines have achieved remarkable progress in treating patients with various tumors in clinical studies. Nevertheless, extensive research has also revealed that tumor vaccines are not up to expectations for the treatment of solid tumors due to their low immunogenicity. Therefore, there is an urgent need to design a tumor vaccine that can stimulate a broad anti-tumor immune response. Methods: In this work, we developed a nanovaccine (NP-TCL@APS), which includes nanoparticles loaded with colorectal cancer tumor cell lysates (TCL) and Astragalus polysaccharides (APS) into poly (lactic-co-glycolic acid) to induce a robust innate immune response. The NP-TCL@APS was identified by transmission electron microscopy and Malvern laser particle size analyzer. The killing and immune activation effects of NP-TCL@APS were evaluated in vitro. Finally, safety and anti-tumor efficacy were evaluated in the colorectal cancer tumor-bearing mouse model. Results: We found that NP-TCL@APS was preferentially uptaken by DC and further promoted the activation of DC in vitro. Additionally, nanoparticles codelivery of TCL and APS enhanced the antigen-specific CD8+ T cell response and suppressed the growth of tumors in mouse models with good biocompatibility. Conclusion: We successfully prepared a nanovaccine termed NP-TCL@APS, which can promote the maturation of DC and induce strong responses by T lymphocytes to exert anti-tumor effects. The strategy proposed here is promising for generating a tumor vaccine and can be extended to various types of cancers.
Assuntos
Vacinas Anticâncer , Neoplasias Colorretais , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Polissacarídeos , Neoplasias Colorretais/terapia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/tratamento farmacológico , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Humanos , Camundongos , Nanopartículas/química , Linhagem Celular Tumoral , Astrágalo/química , Camundongos Endogâmicos BALB C , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Feminino , NanovacinasRESUMO
BACKGROUND: Tumor neoantigen peptide-based vaccines, systemic immunotherapies that enhance antitumor immunity by activating and expanding antigen-specific T cells, have achieved remarkable results in the treatment of a variety of solid tumors. However, how to effectively deliver neoantigens to induce robust antitumor immune responses remains a major obstacle. RESULTS: Here, we developed a safe and effective neoantigen peptide delivery system (neoantigen-ferritin nanoparticles, neoantigen-FNs) that successfully achieved effective lymph node targeting and induced robust antitumor immune responses. The genetically engineered self-assembled particles neoantigen-FNs with a size of 12 nm were obtained by fusing a neoantigen with optimized ferritin, which rapidly drainage to and continuously accumulate in lymph nodes. The neoantigen-FNs vaccine induced a greater quantity and quality of antigen-specific CD8+ T cells and resulted in significant growth control of multiple tumors, dramatic inhibition of melanoma metastasis and regression of established tumors. In addition, no obvious toxic side effects were detected in the various models, indicating the high safety of optimized ferritin as a vaccine carrier. CONCLUSIONS: Homogeneous and safe neoantigen-FNs could be a very promising system for neoantigen peptide delivery because of their ability to efficiently drainage to lymph nodes and induce efficient antitumor immune responses.