RESUMEN
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.
Asunto(s)
Vacunas contra el Cáncer , Desoxicitidina , Resistencia a Antineoplásicos , Gemcitabina , Inmunoterapia , Nanopartículas , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/farmacología , Animales , Inmunoterapia/métodos , Resistencia a Antineoplásicos/efectos de los fármacos , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Nanopartículas/química , Ratones , Humanos , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Línea Celular Tumoral , Ratones Endogámicos C57BL , Femenino , Imidazoles/farmacología , Imidazoles/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Antígenos de Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , NanovacunasRESUMEN
Tumor vaccines have become a promising approach for cancer treatment by triggering antigen-specific responses against tumors. However, autophagy and immunosuppressive tumor microenvironment (TME) reduce antigen exposure and immunogenicity, which limit the effect of tumor vaccines. Here, we develop fucoidan (Fuc) based chlorin e6 (Ce6)-chloroquine (CQ) self-assembly hydrogels (CCFG) as in situ vaccines. Ce6 triggers immune response in situ by photodynamic therapy (PDT) induced immunogenic cell death (ICD) effect, which is further enhanced by macrophage polarization of Fuc and autophagy inhibition of CQ. In vivo studies show that CCFG effectively enhances antigen presentation under laser irradiation, which induces a powerful in situ vaccine effect and significantly inhibits tumor metastasis and recurrence. Our study provides a novel approach for enhancing tumor immunotherapy and inhibiting tumor recurrence and metastasis.
Asunto(s)
Autofagia , Vacunas contra el Cáncer , Clorofilidas , Cloroquina , Hidrogeles , Inmunoterapia , Macrófagos , Fotoquimioterapia , Polisacáridos , Porfirinas , Animales , Polisacáridos/farmacología , Polisacáridos/química , Ratones , Vacunas contra el Cáncer/farmacología , Vacunas contra el Cáncer/inmunología , Porfirinas/química , Porfirinas/farmacología , Porfirinas/uso terapéutico , Autofagia/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Inmunoterapia/métodos , Fotoquimioterapia/métodos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Cloroquina/farmacología , Ratones Endogámicos C57BL , Microambiente Tumoral/efectos de los fármacos , Células RAW 264.7 , Línea Celular Tumoral , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Ratones Endogámicos BALB C , FemeninoRESUMEN
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.
Asunto(s)
Linfocitos T CD8-positivos , Vacunas contra el Cáncer , Inmunoterapia , Liposomas , Ratones Endogámicos C57BL , Animales , Liposomas/química , Ratones , Femenino , Inmunoterapia/métodos , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Línea Celular Tumoral , Nanopartículas/química , Neoplasias/inmunología , Neoplasias/terapia , Humanos , NanovacunasRESUMEN
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.
Asunto(s)
Antígenos de Neoplasias , Vacunas contra el Cáncer , Células Dendríticas , Animales , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/administración & dosificación , Ratones , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Humanos , Células Dendríticas/inmunología , Vacunas de Partículas Similares a Virus/inmunología , Vacunas de Partículas Similares a Virus/administración & dosificación , Vacunas de Partículas Similares a Virus/genética , Proteínas de la Cápside/inmunología , Proteínas de la Cápside/genética , Péptidos/inmunología , Femenino , Ratones Endogámicos C57BL , Línea Celular Tumoral , VacunaciónRESUMEN
The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless cancer therapy and overcome immunosuppression in cancers.
Asunto(s)
Mitocondrias , Neoplasias , Microambiente Tumoral , Animales , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratones , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Humanos , Línea Celular Tumoral , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/inmunología , Apoptosis/efectos de los fármacos , Femenino , Muerte Celular Inmunogénica/efectos de los fármacos , Ratones Endogámicos C57BL , Nanopartículas/química , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Inmunoterapia/métodosRESUMEN
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.
Asunto(s)
Antígenos de Neoplasias , Inmunoterapia , Proteínas de la Membrana , Neoplasias , Humanos , Antígenos de Neoplasias/inmunología , Inmunoterapia/métodos , Neoplasias/terapia , Neoplasias/inmunología , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Vacunas contra el Cáncer/inmunologíaRESUMEN
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.
Asunto(s)
Antígenos de Neoplasias , Vacunas contra el Cáncer , Ferritinas , Ratones Endogámicos C57BL , Nanopartículas , Animales , Ferritinas/química , Antígenos de Neoplasias/inmunología , Nanopartículas/química , Vacunas contra el Cáncer/inmunología , Ratones , Línea Celular Tumoral , Linfocitos T CD8-positivos/inmunología , Femenino , Inmunoterapia/métodos , Metástasis de la Neoplasia , Humanos , Ganglios Linfáticos , Proteínas RecombinantesRESUMEN
Despite the increasing number of studies on nanomedicine-based cancer immunotherapy, the overall research trends in this field remain inadequately characterized. This study aims to evaluate the research trends and hotspots in nanomedicine-based cancer immunotherapy through a bibliometric analysis. As of March 31, 2024, relevant publications were retrieved from the Web of Science Core Collection. Analytical tools including VOSviewer, CiteSpace, and an online bibliometric analysis platform were employed. A total of 5,180 publications were analyzed. The study reveals geographical disparities in research output, with China and the United States being the leading contributors. Institutionally, the Chinese Academy of Sciences, University of Chinese Academy of Sciences, and Sichuan University are prominent contributors. Authorship analysis identifies key researchers, with Liu Zhuang being the most prolific author. "ACS Nano" and the "Journal of Controlled Release and Biomaterials" are identified as the leading journals in the field. Frequently occurring keywords include "cancer immunotherapy" and "drug delivery." Emerging frontiers in the field, such as "mRNA vaccine," "sonodynamic therapy," "oral squamous cell carcinoma," "STING pathway,"and "cGAS-STING pathway," are experiencing rapid growth. This study aims to provide new insights to advance scientific research and clinical applications in nanomedicine-based cancer immunotherapy.
Asunto(s)
Bibliometría , Inmunoterapia , Nanomedicina , Neoplasias , Humanos , Inmunoterapia/métodos , Neoplasias/terapia , Neoplasias/inmunología , Animales , Vacunas contra el Cáncer/uso terapéuticoRESUMEN
With the COVID-19 pandemic, the importance of vaccines has been widely recognized and has led to increased research and development efforts. Vaccines also play a crucial role in cancer treatment by activating the immune system to target and destroy cancer cells. However, enhancing the efficacy of cancer vaccines remains a challenge. Adjuvants, which enhance the immune response to antigens and improve vaccine effectiveness, have faced limitations in recent years, resulting in few novel adjuvants being identified. The advancement of artificial intelligence (AI) technology in drug development has provided a foundation for adjuvant screening and application, leading to a diversification of adjuvants. This article reviews the significant role of tumor vaccines in basic research and clinical treatment and explores the use of AI technology to screen novel adjuvants from databases. The findings of this review offer valuable insights for the development of new adjuvants for next-generation vaccines.
Asunto(s)
Adyuvantes Inmunológicos , Inteligencia Artificial , COVID-19 , Vacunas contra el Cáncer , Neoplasias , Humanos , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Neoplasias/inmunología , Neoplasias/terapia , COVID-19/prevención & control , COVID-19/inmunología , SARS-CoV-2/inmunología , Animales , Desarrollo de Vacunas , Desarrollo de MedicamentosRESUMEN
We have previously reported two single-agent phase I trials, evaluating the dose or schedule, of a DNA vaccine (pTVG-HP) encoding prostatic acid phosphatase (PAP) administered with GM-CSF as the adjuvant. These were in patients with PSA-recurrent, radiographically non-metastatic, prostate cancer (PCa). We report here the long-term safety and overall survival of these patients. Specifically, 22 patients with non-metastatic, castration-sensitive PCa (nmCSPC) were treated with pTVG-HP, 100-1500 µg, administered over 12 weeks and followed for 15 y. 17 patients with non-metastatic castration-resistant PCa (nmCRPC) were treated with 100 µg pTVG-HP with different schedules of administration over 1 y and followed for 5 y. No adverse events were detected in long-term follow-up from either trial that were deemed possibly related to vaccination. Patients with nmCSPC had a median overall survival of 12.3 y, with 5/22 (23%) alive at 15 y. 8/22 (36%) died due to prostate cancer with a median survival of 11.0 y, and 9/22 (41%) died of other causes. Patients with nmCRPC had a median overall survival of 4.5 y, with 8/17 (47%) alive at 5 y. The presence of T-cells specific for the PAP target antigen was detectable in 6/10 (60%) individuals with nmCSPC, and 3/5 (60%) individuals with nmCRPC, many years after immunization. The detection of immune responses to the vaccine target years after immunization suggests durable immunity can be elicited in patients using a DNA vaccine encoding a tumor-associated antigen.Trial Registration: NCT00582140 and NCT00849121.
Asunto(s)
Vacunas contra el Cáncer , Antígeno Prostático Específico , Neoplasias de la Próstata , Vacunas de ADN , Humanos , Masculino , Vacunas de ADN/inmunología , Vacunas de ADN/administración & dosificación , Vacunas de ADN/efectos adversos , Antígeno Prostático Específico/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/administración & dosificación , Anciano , Estudios de Seguimiento , Neoplasias de la Próstata/inmunología , Persona de Mediana Edad , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/efectos adversos , Resultado del Tratamiento , Anciano de 80 o más Años , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Recurrencia Local de Neoplasia , Análisis de Supervivencia , Fosfatasa Ácida , Proteínas Tirosina Fosfatasas/inmunologíaRESUMEN
BACKGROUND: Gliomas, particularly glioblastoma multiforme (GBM), are highly aggressive brain tumors that present significant challenges in oncology due to their rapid progression and resistance to conventional therapies. Despite advancements in treatment, the prognosis for patients with GBM remains poor, necessitating the exploration of novel therapeutic approaches. One such emerging strategy is the development of glioma vaccines, which aim to stimulate the immune system to target and destroy tumor cells. AIMS: This review aims to provide a comprehensive evaluation of the current landscape of glioma vaccine development, analyzing the types of vaccines under investigation, the outcomes of clinical trials, and the challenges and opportunities associated with their implementation. The goal is to highlight the potential of glioma vaccines in advancing more effective and personalized treatments for glioma patients. MATERIALS AND METHODS: This narrative review systematically assessed the role of glioma vaccines by including full-text articles published between 2000 and 2024 in English. Databases such as PubMed/MEDLINE, EMBASE, the Cochrane Library, and Scopus were searched using key terms like "glioma," "brain tumor," "glioblastoma," "vaccine," and "immunotherapy." The review incorporated both pre-clinical and clinical studies, including descriptive studies, animal-model studies, cohort studies, and observational studies. Exclusion criteria were applied to omit abstracts, case reports, posters, and non-peer-reviewed studies, ensuring the inclusion of high-quality evidence. RESULTS: Clinical trials investigating various glioma vaccines, including peptide-based, DNA/RNA-based, whole-cell, and dendritic-cell vaccines, have shown promising results. These vaccines demonstrated potential in extending survival rates and managing adverse events in glioma patients. However, significant challenges remain, such as therapeutic resistance due to tumor heterogeneity and immune evasion mechanisms. Moreover, the lack of standardized guidelines for evaluating vaccine responses and issues related to ethical considerations, regulatory hurdles, and vaccine acceptance among patients further complicate the implementation of glioma vaccines. DISCUSSION: Addressing the challenges associated with glioma vaccines involves exploring combination therapies, targeted approaches, and personalized medicine. Combining vaccines with traditional therapies like radiotherapy or chemotherapy may enhance efficacy by boosting the immune system's ability to fight tumor cells. Personalized vaccines tailored to individual patient profiles present an opportunity for improved outcomes. Furthermore, global collaboration and equitable distribution are critical for ensuring access to glioma vaccines, especially in low- and middle-income countries with limited healthcare resources CONCLUSION: Glioma vaccines represent a promising avenue in the fight against gliomas, offering hope for improving patient outcomes in a disease that is notoriously difficult to treat. Despite the challenges, continued research and the development of innovative strategies, including combination therapies and personalized approaches, are essential for overcoming current barriers and transforming the treatment landscape for glioma patients.
Asunto(s)
Neoplasias Encefálicas , Vacunas contra el Cáncer , Glioma , Inmunoterapia , Animales , Humanos , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Vacunas contra el Cáncer/uso terapéutico , Vacunas contra el Cáncer/inmunología , Glioma/inmunología , Glioma/terapia , Inmunoterapia/métodos , Inmunoterapia/tendenciasRESUMEN
Fibrosarcoma, a malignant mesenchymal tumor, is characterized by aggressive invasiveness and a high recurrence rate, leading to poor prognosis. Anthracycline drugs, such as doxorubicin (DOX), represent the frontline chemotherapy for fibrosarcoma, but often exhibit suboptimal efficacy. Recently, exploiting the stimulator of interferon genes (STING)-mediated innate immunity has emerged as a hopeful strategy for cancer treatment. Integrating chemotherapy with immunomodulators in chemo-immunotherapy has shown potential for enhancing treatment outcomes. Herein, we introduce an advanced dendritic cell (DC) nanovaccine, cGAMP@PLGA@CRTM (GP@CRTM), combined with low-dose DOX to enhance fibrosarcoma chemo-immunotherapy. The nanovaccine consists of poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating the STING agonist 2,3-cGAMP (cGAMP@PLGA, GP) as its core, and a calreticulin (CRT) high-expressing fibrosarcoma cell membrane (CRTM) as the shell. Exposing CRT on the vaccine surface aids in recruiting DCs and stimulating uptake, facilitating efficient simultaneous delivery of STING agonists and tumor antigens to DCs. This dual delivery method effectively activates the STING pathway in DCs, triggering sustained immune stimulation. Simultaneously, low-dose DOX reduces chemotherapy-related side effects, directly kills a subset of tumor cells, and increases tumor immunogenicity, thus further amplifying immune therapeutic performance. Hence, these findings demonstrate the potential of DC nanovaccine GP@CRTM as a booster for chemotherapy. Synergistically combining low-dose DOX with the DC nanovaccine emerges as a powerful chemo-immunotherapy strategy, optimizing systemic fibrosarcoma therapy.
Asunto(s)
Vacunas contra el Cáncer , Células Dendríticas , Doxorrubicina , Fibrosarcoma , Nanopartículas , Nucleótidos Cíclicos , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Fibrosarcoma/tratamiento farmacológico , Fibrosarcoma/patología , Fibrosarcoma/inmunología , Fibrosarcoma/terapia , Animales , Doxorrubicina/farmacología , Doxorrubicina/química , Ratones , Nucleótidos Cíclicos/química , Nucleótidos Cíclicos/farmacología , Nanopartículas/química , Vacunas contra el Cáncer/inmunología , Humanos , Proteínas de la Membrana/metabolismo , Línea Celular Tumoral , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Ratones Endogámicos C57BL , Inmunoterapia , Calreticulina/metabolismo , NanovacunasRESUMEN
BACKGROUND: In this study, effective antigens of mRNA vaccine were excavated from the perspective of ICD, and ICD subtypes of PRAD were further distinguished to establish an ICD landscape, thereby determining suitable vaccine recipients. RESEARCH DESIGN AND METHODS: TCGA and MSKCC databases were applied to acquire RNA-seq data and corresponding clinical data of 554 and 131 patients, respectively. GEPIA was employed to measure prognostic indices. Then, a comparison of genetic alterations was performed utilizing cBioPortal, and correlation of identified ICD antigens with immune infiltrating cells was analyzed employing TIMER. Moreover, ICD subtypes were identified by means of consensus cluster, and ICD landscape of PRAD was depicted utilizing graph learning-based dimensional reduction. RESULTS: In total, 4 PRAD antigens were identified in PRAD, including FUS, LMNB2, RNPC3, and ZNF700, which had association with adverse prognosis and infiltration of APCs. PRAD patients were classified as two ICD subtypes based on their differences in molecular, cellular, and clinical features. Furthermore, ICD modulators and immune checkpoints were also differentially expressed between two ICD subtype tumors. Finally, the ICD landscape of PRAD showed substantial heterogeneity among individual patients. CONCLUSIONS: In summary, the research may provide a theoretical foundation for developing mRNA vaccine against PRAD as well as determining appropriate vaccine recipients.
Asunto(s)
Adenocarcinoma , Antígenos de Neoplasias , Vacunas contra el Cáncer , Muerte Celular Inmunogénica , Neoplasias de la Próstata , Vacunas de ARNm , Humanos , Neoplasias de la Próstata/inmunología , Masculino , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Antígenos de Neoplasias/inmunología , Adenocarcinoma/inmunología , PronósticoRESUMEN
Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.
Asunto(s)
Vacunas contra el Cáncer , Macroglobulinemia de Waldenström , Humanos , Masculino , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Vacunas contra el Cáncer/administración & dosificación , Persona de Mediana Edad , Femenino , Macroglobulinemia de Waldenström/inmunología , Macroglobulinemia de Waldenström/terapia , Macroglobulinemia de Waldenström/genética , Anciano , Microambiente Tumoral/inmunología , Medicina de Precisión/métodos , Vacunas de ADN/inmunología , Vacunas de ADN/uso terapéutico , Antígenos de Neoplasias/inmunología , Linfocitos B/inmunologíaAsunto(s)
Neoplasias del Sistema Nervioso Central , Humanos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Inmunoterapia Adoptiva , Proyectos Piloto , Productos Biológicos/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Linfoma/tratamiento farmacológico , Linfoma/diagnósticoRESUMEN
Therapeutic vaccine becomes a promising strategy to fight cancer by enhancing and sustaining specific anti-tumor immune responses. However, its efficacy is often impeded by low immunogenicity, the immunosuppressive tumor microenvironment (TME), and immune-related adverse events. Herein, we introduce 1-tetradecanol (TD)-wrapped, CpG-loaded porous Prussian blue nanoparticles (pPBNPs-CpG@TD) as a nanoimmunomodulator to initiate photothermal-induced immunogenic cell death (ICD) and photothermal-responsive release of CpG for augmenting the ICD effect. It was revealed that the dual-photothermal action significantly potentiated the in situ anti-tumor vaccine-like immunotherapy in terms of enhanced immunogenicity, promoted dendritic cell maturation, and increased T lymphocyte infiltration, consequently eliciting a robust immune response for inhibiting both primary and rechallenge tumors on a subcutaneous 4T1 tumor-bearing mouse model. The development and use of photoactive nanoimmunomodulators represents a novel and effective strategy to boost immunogenicity and counteract immunosuppressive TME, marking a significant advancement in the realm of ICD-driven in situ anti-tumor vaccine-like immunotherapy.
Asunto(s)
Vacunas contra el Cáncer , Ferrocianuros , Inmunoterapia , Nanopartículas , Animales , Ferrocianuros/química , Inmunoterapia/métodos , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Ratones , Nanopartículas/química , Línea Celular Tumoral , Porosidad , Femenino , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Terapia Fototérmica/métodos , Ratones Endogámicos BALB C , Células Dendríticas/inmunología , Humanos , Factores Inmunológicos/farmacología , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/química , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/farmacología , Oligodesoxirribonucleótidos/químicaRESUMEN
Effective activation of an antigen-specific immune response hinges upon the intracellular delivery of cancer antigens to antigen-presenting cells (APCs), marking the initial stride in cancer vaccine development. Leveraging biomimetic topological morphology, we employed virus-like mesoporous silica nanoparticles (VMSNs) coloaded with antigens and toll-like receptor 9 (TLR9) agonists to craft a potent cancer vaccine. Our VMSNs could be efficiently internalized by APCs to a greater extent than their nonviral structured counterparts, thereby promoting the activation of APCs by upregulating the TLR9 pathway and cross-presenting ovalbumin (OVA) epitopes. In in vivo animal study, VMSN-based nanovaccines triggered substantial CD4+ and CD8+ lymphocyte populations in both lymph nodes and spleen while inducing the effector memory of adaptive T cells. Consequently, VMSN-based nanovaccines suppressed tumor progression and increased the survival rate of B16-OVA-bearing mice in both prophylactic and therapeutic studies. The combination of immune checkpoint blockade (ICB) with the VMSN-based nanovaccine has synergistic effects in significantly preventing tumor progression under therapeutic conditions. These findings highlight the potential of viral structure-mimicking mesoporous silica nanoparticles as promising candidates for antigen-delivering nanocarriers in vaccine development.
Asunto(s)
Ratones Endogámicos C57BL , Nanopartículas , Dióxido de Silicio , Dióxido de Silicio/química , Animales , Nanopartículas/química , Ratones , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/química , Ovalbúmina/química , Ovalbúmina/inmunología , Porosidad , Inmunidad Adaptativa/efectos de los fármacos , Humanos , Células Presentadoras de Antígenos/inmunología , Neoplasias/inmunología , Femenino , Receptor Toll-Like 9/inmunología , Receptor Toll-Like 9/agonistas , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/química , Línea Celular TumoralRESUMEN
Gliomas are one of the most aggressive types of brain tumors and are associated with high morbidity and mortality rates. Currently, conventional treatments for gliomas such as surgical resection, radiotherapy, and chemotherapy have limited effectiveness, and new approaches are needed to improve patient outcomes. mRNA-based vaccines represent a promising therapeutic strategy for cancer treatment, including gliomas. Recent advances in immunotherapy using mRNA-based dendritic cell vaccines have shown great potential in preclinical and clinical trials. Dendritic cells are professional antigen-presenting cells that play a crucial role in initiating and regulating immune responses. In this review, we summarize the current progress of mRNA-based vaccines for gliomas, with a focus on recent advances in dendritic cell-based mRNA vaccines. We also discuss the feasibility and safety of mRNA-based clinical applications for gliomas.