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1.
Nat Commun ; 12(1): 5195, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465781

RESUMO

Functional tumor-specific cytotoxic T cells elicited by therapeutic cancer vaccination in combination with oncolytic viruses offer opportunities to address resistance to checkpoint blockade therapy. Two cancer vaccines, the self-adjuvanting protein vaccine KISIMA, and the recombinant oncolytic vesicular stomatitis virus pseudotyped with LCMV-GP expressing tumor-associated antigens, termed VSV-GP-TAA, both show promise as a single agent. Here we find that, when given in a heterologous prime-boost regimen with an optimized schedule and route of administration, combining KISIMA and VSV-GP-TAA vaccinations induces better cancer immunity than individually. Using several mouse tumor models with varying degrees of susceptibility for viral replication, we find that priming with KISIMA-TAA followed by VSV-GP-TAA boost causes profound changes in the tumor microenvironment, and induces a large pool of poly-functional and persistent antigen-specific cytotoxic T cells in the periphery. Combining this heterologous vaccination with checkpoint blockade further improves therapeutic efficacy with long-term survival in the spectrum. Overall, heterologous vaccination with KISIMA and VSV-GP-TAA could sensitize non-inflamed tumors to checkpoint blockade therapy.


Assuntos
Vacinas Anticâncer/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Vírus Oncolíticos/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Terapia Combinada , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Vírus Oncolíticos/fisiologia , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral , Vacinação , Vírus da Estomatite Vesicular Indiana/genética , Vírus da Estomatite Vesicular Indiana/fisiologia , Replicação Viral
2.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445092

RESUMO

Dendritic cells (DCs) are the most effective antigen presenting cells for the development of T cell responses. The only FDA approved DC-based immunotherapy to date is Sipuleucel-T, which utilizes a fusion protein to stimulate DCs ex vivo with GM-CSF and simultaneously deliver the antigen PAP for prostate cancer. This approach is restricted by the breadth of immunity elicited to a single antigen, and to cancers that have a defined tumor associated antigen. Other multi-antigen approaches have been restricted by poor efficacy of vaccine adjuvants. We have developed a vaccine platform that consists of autologous DCs pulsed with cytokine-adjuvanted tumor membrane vesicles (TMVs) made from tumor tissue, that encapsulate the antigenic landscape of individual tumors. Here we test the efficacy of DCs pulsed with TMVs incorporated with glycolipid-anchored immunostimulatory molecules (GPI-ISMs) in HER2-positive and triple negative breast cancer murine models. Pulsing of DCs with TMVs containing GPI-ISMs results in superior uptake of vesicles, DC activation and cytokine production. Adaptive transfer of TMV-pulsed DCs to tumor bearing mice results in the inhibition of tumor growth, reduction in lung metastasis, and an increase in immune cell infiltration into the tumors. These observations suggest that DCs pulsed with TMVs containing GPI-GM-CSF and GPI-IL-12 can be further developed to be used as a personalized immunotherapy platform for cancer treatment.


Assuntos
Antígenos de Neoplasias/imunologia , Citocinas/imunologia , Células Dendríticas/imunologia , Receptor ErbB-2/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Transferência Adotiva , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Receptor ErbB-2/análise , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia
3.
Nat Commun ; 12(1): 4734, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354077

RESUMO

The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated a Cxcl13-expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation of Il33 gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells.


Assuntos
Melanoma Experimental/terapia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Técnicas de Reprogramação Celular/métodos , Quimiocina CXCL13/genética , Quimiocina CXCL13/imunologia , Feminino , Vetores Genéticos , Interleucina-33/deficiência , Interleucina-33/genética , Interleucina-33/imunologia , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Vírus da Coriomeningite Linfocítica/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/imunologia
4.
Nat Commun ; 12(1): 4964, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400628

RESUMO

Immunological adjuvants are essential for successful cancer vaccination. However, traditional adjuvants have some limitations, such as lack of controllability and induction of systemic toxicity, which restrict their broad application. Here, we present a light-activable immunological adjuvant (LIA), which is composed of a hypoxia-responsive amphiphilic dendrimer nanoparticle loaded with chlorin e6. Under irradiation with near-infrared light, the LIA not only induces tumour cell lysis and tumour antigen release, but also promotes the structural transformation of 2-nitroimidazole containing dendrimer to 2-aminoimidazole containing dendrimer which can activate dendritic cells via the Toll-like receptor 7-mediated signaling pathway. The LIA efficiently inhibits both primary and abscopal tumour growth and induces strong antigen-specific immune memory effect to prevent tumour metastasis and recurrence in vivo. Furthermore, LIA localizes the immunological adjuvant effect at the tumour site. We demonstrate this light-activable immunological adjuvant offers a safe and potent platform for in situ cancer vaccination.


Assuntos
Adjuvantes Imunológicos/farmacologia , Vacinas Anticâncer/imunologia , Dendrímeros/farmacologia , Vacinação , Animais , Antígenos de Neoplasias , Antitussígenos , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Humanos , Hipóxia , Imunoterapia , Luz , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Nanopartículas/química , Metástase Neoplásica/prevenção & controle , Recidiva Local de Neoplasia , Neoplasias/genética , Neoplasias/prevenção & controle , Porfirinas , Transcriptoma
5.
Front Immunol ; 12: 711565, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335627

RESUMO

Extracellular vesicles (EVs) are released by most cell types as part of an intracellular communication system in crucial processes such as inflammation, cell proliferation, and immune response. However, EVs have also been implicated in the pathogenesis of several diseases, such as cancer and numerous infectious diseases. An important feature of EVs is their ability to deliver a wide range of molecules to nearby targets or over long distances, which allows the mediation of different biological functions. This delivery mechanism can be utilized for the development of therapeutic strategies, such as vaccination. Here, we have highlighted several studies from a historical perspective, with respect to current investigations on EV-based vaccines. For example, vaccines based on exosomes derived from dendritic cells proved to be simpler in terms of management and cost-effectiveness than dendritic cell vaccines. Recent evidence suggests that EVs derived from cancer cells can be leveraged for therapeutics to induce strong anti-tumor immune responses. Moreover, EV-based vaccines have shown exciting and promising results against different types of infectious diseases. We have also summarized the results obtained from completed clinical trials conducted on the usage of exosome-based vaccines in the treatment of cancer, and more recently, coronavirus disease.


Assuntos
COVID-19/imunologia , Vacinas Anticâncer/imunologia , Exossomos/imunologia , Vesículas Extracelulares/imunologia , Neoplasias/imunologia , SARS-CoV-2/fisiologia , Vacinas/imunologia , Animais , Ensaios Clínicos como Assunto , Humanos , Imunidade , Imunização
6.
Anticancer Res ; 41(7): 3419-3427, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230137

RESUMO

BACKGROUND/AIM: Liver metastases are among the principal mortality causes in cancer patients. Dendritic cell immunotherapies have shown promising results in some tumors by mediating immunological mechanisms that could be involved in liver metastases during primary tumor growth. The present study aimed to evaluate the impact of prophylactic dendritic cell vaccination on the liver of mice with 4T1 mouse breast carcinoma. MATERIALS AND METHODS: Adult female Balb/c mice were submitted or not to vaccination with dendritic cells before the induction of 4T1 tumor lineage. Liver tissues from mice were analyzed by flow cytometry (markers CD3, CD4, CD8, CD25, IL-10, IL-12, IL-17, TNF-α, IFN-γ, T-bet, GATA3, RORγt, and FoxP3) and hematoxylin-eosin. The dendritic cell vaccine was differentiated and matured ex vivo from the bone marrow. RESULTS: Prophylactic vaccination reduced areas of liver metastases (p=0.0049), induced an increase in the percentage of total T and cytotoxic T lymphocytes (p<0.0001), as well as FoxP3+ (p<0.0001). It also increased the levels of cytokines IL-10 and IL-17 in helper T lymphocytes (p<0.0001). CONCLUSION: The prophylactic dendritic cell vaccine changed the cell phenotype in the immune response of liver, and it was able to reduce metastases. Cytotoxic T cells and regulatory T lymphocytes were more present, likewise, the production of IL-10 and IL-7 simultaneously, demonstrating that the vaccine can induce a state of control of pro-inflammatory responses, which can provide a less favorable environment for metastatic tumor growth.


Assuntos
Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Neoplasias Hepáticas/imunologia , Fígado/imunologia , Animais , Biomarcadores Tumorais/imunologia , Medula Óssea/imunologia , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Feminino , Imunidade/imunologia , Imunoterapia/métodos , Fígado/patologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Vacinação/métodos
7.
Front Immunol ; 12: 679344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305909

RESUMO

Recently, mRNA vaccines have become a significant type of therapeutic and have created new fields in the biopharmaceutical industry. mRNA vaccines are promising next-generation vaccines that have introduced a new age in vaccinology. The recent approval of two COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) has accelerated mRNA vaccine technology and boosted the pharmaceutical and biotechnology industry. These mRNA vaccines will help to tackle COVID-19 pandemic through immunization, offering considerable hope for future mRNA vaccines. Human trials with data both from mRNA cancer vaccines and mRNA infectious disease vaccines have provided encouraging results, inspiring the pharmaceutical and biotechnology industries to focus on this area of research. In this article, we discuss current mRNA vaccines broadly in two parts. In the first part, mRNA vaccines in general and COVID-19 mRNA vaccines are discussed. We presented the mRNA vaccine structure in general, the different delivery systems, the immune response, and the recent clinical trials for mRNA vaccines (both for cancer mRNA vaccines and different infectious diseases mRNA vaccines). In the second part, different COVID-19 mRNA vaccines are explained. Finally, we illustrated a snapshot of the different leading mRNA vaccine developers, challenges, and future prospects of mRNA vaccines.


Assuntos
Vacinas contra COVID-19/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Desenvolvimento de Medicamentos , Vacinas Sintéticas/uso terapêutico , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos , Humanos , Imunidade , Neoplasias/imunologia , Neoplasias/terapia , SARS-CoV-2/imunologia , Vacinação , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
8.
Theranostics ; 11(14): 6936-6949, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093863

RESUMO

Substantial progress has been made with cancer immunotherapeutic strategies in recent years, most of which mainly rely on enhancing the T cell response. However, sufficient tumor antigen information often cannot be presented to T cells, resulting in a failed effector T cell response. The innate immune system can effectively recognize tumor antigens and then initiate an adaptive immune response. Here, we developed a spontaneous multifunctional hydrogel (NOCC-CpG/OX-M, Ncom Gel) vaccine to amplify the innate immune response and harness innate immunity to launch and maintain a powerful adaptive immune response. Methods: Ncom Gel was formed by a Schiff base reaction between CpG-modified carboxymethyl chitosan (NOCC-CpG) and partially oxidized mannan (OX-M). The effects of the Ncom Gel vaccine on DCs and macrophages in vitro and antigen-specific humoral immunity and cellular immunity in vivo were studied. Furthermore, the antitumor immune response of the Ncom Gel vaccine and its effect on the tumor microenvironment were evaluated. Results: The Ncom Gel vaccine enhanced antigen presentation to T cells by facilitating DC uptake and maturation and inducing macrophages to a proinflammatory subtype, further leading to a T cell-mediated adaptive immune response. Moreover, the innate immune response could be amplified via the promotion of antigen-specific antibody production. The Ncom Gel vaccine reversed the tumor immune microenvironment to an inflamed phenotype and showed a significant antitumor response in a melanoma model. Conclusions: Our research implies the potential application of injectable hydrogels as a platform for tumor immunotherapy. The strategy also opens up a new avenue for multilayered cancer immunotherapy.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Vacinas Anticâncer/imunologia , Hidrogéis/química , Hidrogéis/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunoterapia/métodos , Melanoma/imunologia , Microambiente Tumoral/efeitos dos fármacos , Imunidade Adaptativa/imunologia , Animais , Linhagem Celular Tumoral , Quitosana/química , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Hidrogéis/síntese química , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Mananas/química , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Ovalbumina/imunologia , Reologia , Bases de Schiff/química , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
9.
Theranostics ; 11(15): 7425-7438, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158858

RESUMO

The lack of tumor specific antigens (TSA) and the immune tolerance are two major obstacles for the immunotherapy of cancer. Current immune checkpoint inhibitors (ICIs) show clinical responses in only limited subsets of cancer patients, which, to some extent, depends on the mutation load of tumor cells that may generate neoantigens. Here, we aimed to generate a neoantigen MDP to exhibit stronger anti-tumor efficacy. Methods: In this study, we utilized chemically modified sialic acid precursor tetra acetyl-N-azidoacetyl-mannosamine (AC4ManNAZ) to engineer the glycoproteins on the membranes of tumor cells for the covalent ligation of hapten adjuvant Pam3CSK4 in vivo, which eventually generated a neoantigen, i.e., ManNAZ-DBCO-Pam3CSK4 (MDP), on tumor cells. The high labeling efficiency, relatively specific biodistribution in tumor tissues and the anti-tumor efficacy were confirmed in the syngeneic murine models of the breast cancer and the lung cancer. Results: The generation of MDP neoantigen in tumor-bearing mice significantly evoked both the humoral and the T-cell-dependent antitumor immune responses, resulting in a strong inhibition on the growth of the breast cancer and the lung cancer allografts and significantly prolonged survival of tumor-bearing mice. Interestingly, MDP neoantigen was able to dramatically increase the sensitivity of cancer cells to ICIs and greatly enhance the anti-tumor efficacy in the murine models of both breast cancer and the lung cancer, which showed no or low responses to the immunotherapy with anti-PD1 antibody alone. Conclusions: We developed a simple metabolic glycoengineering method to artificially generate neoantigens on tumor cells to enhance tumor cell immunogenicity, which is able to significantly improve the response and the clinical outcome of ICIs.


Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Glicoproteínas , Lipopeptídeos , Neoplasias Mamárias Experimentais , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/farmacologia , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Linhagem Celular Tumoral , Feminino , Glicoproteínas/química , Glicoproteínas/imunologia , Glicoproteínas/farmacologia , Lipopeptídeos/química , Lipopeptídeos/imunologia , Lipopeptídeos/farmacologia , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Camundongos
10.
Theranostics ; 11(15): 7308-7321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158852

RESUMO

Dendritic cells (DCs) can process the antigens of cancer vaccine and thus stimulate the CD8+ T cells to recognize and kill the tumor cells that express these antigens. However, lack of promising carriers for presenting the antigens to DCs is one of the main barriers to the development of clinically effective cancer vaccines. Another limitation is the risk of inflammatory side effects induced by the adjuvants. It is still unclear how we can develop ideal adjuvant-free DC vaccine carriers without adjuvants. Methods: A 12-mer peptide carrier (CBP-12) with high affinity for Clec9a expressed on DCs was developed using an in silico rational optimization method. The therapeutic effects of the adjuvant-free vaccine comprising CBP-12 and exogenous or endogenous antigenic peptides were investigated in terms of antigen cross-presentation efficacy, specific cytotoxic T lymphocyte response, and antitumor activity. We also explored the mechanism involved in the antitumor effects of the adjuvant-free CBP-12 vaccine. Finally, we assessed the effects of the CBP-12 conjugated peptide vaccine combined with radiotherapy. Results: Here, we developed CBP-12 as a vaccine carrier that enhanced the uptake and cross-presentation of the antigens, thus inducing strong CD8+ T cell responses and antitumor effects in both anti-PD-1-responsive (B16-OVA) and -resistant (B16) models, even in adjuvant-free conditions. CBP-12 bound to and activated Clec9a, thereby stimulating Clec9a+ DC to product IL-21, but not IL-12 by activating of Syk. The antitumor effects of the CBP-12 conjugated peptide vaccines could be blocked by an IL-21 neutralizing antibody. We also observed the synergistic antitumor effects of the CBP-12 conjugated peptide vaccine combined with radiotherapy. Conclusions: CBP-12 could serve as an adjuvant-free peptide vaccine carrier for cancer immunotherapy.


Assuntos
Vacinas Anticâncer , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos , Interleucinas/imunologia , Lectinas Tipo C/imunologia , Melanoma Experimental/imunologia , Peptídeos , Receptores Imunológicos/imunologia , Transdução de Sinais/efeitos dos fármacos , Quinase Syk/imunologia , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Feminino , Interleucinas/genética , Lectinas Tipo C/genética , Melanoma Experimental/genética , Melanoma Experimental/terapia , Camundongos , Camundongos Knockout , Peptídeos/imunologia , Peptídeos/farmacologia , Receptores Imunológicos/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Quinase Syk/genética , Vacinas de Subunidades/imunologia , Vacinas de Subunidades/farmacologia
11.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072360

RESUMO

For many years, oncological clinical trials have taken advantage of dendritic cells (DC) for the design of DC-based cellular therapies. This has required the design of suitable quality control assays to evaluate the potency of these products. The purpose of our work was to develop and validate a novel bioassay that uses flow cytometry as a read-out measurement. In this method, CD3+ cells are labeled with a fluorescent dye and the DC costimulatory activity is measured by the degree of T cell proliferation caused by the DC-T cell interaction. The validation of the method was achieved by the evaluation of essential analytical parameters defined by international guidelines. Our results demonstrated that the method could be considered specific, selective, and robust. The comparison between measured values and estimated true values confirmed a high level of accuracy and a lack of systematic error. Repeated experiments have shown the reproducibility of the assay and the proportionality between the potency and the DC amount has proven its linearity. Our results suggest that the method is compliant with the guidelines and could be adopted as a quality control assay or batch-release testing within GMP facilities.


Assuntos
Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Biomarcadores , Vacinas Anticâncer/uso terapêutico , Citometria de Fluxo/métodos , Humanos , Imunofenotipagem , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Linfócitos T/imunologia , Linfócitos T/metabolismo
12.
Front Immunol ; 12: 642316, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936058

RESUMO

The promise of tumor immunotherapy to significantly improve survival in patients who are refractory to long-standing therapies, such as chemotherapy and radiation, is now being realized. While immune checkpoint inhibitors that target PD-1 and CTLA-4 are leading the charge in clinical efficacy, there are a number of other promising tumor immunotherapies in advanced development such as Listeria-based vaccines. Due to its unique life cycle and ability to induce robust CTL responses, attenuated strains of Listeria monocytogenes (Lm) have been utilized as vaccine vectors targeting both infectious disease and cancer. In fact, preclinical studies in a multitude of cancer types have found Listeria-based vaccines to be highly effective at activating anti-tumor immunity and eradicating tumors. Several clinical trials have now recently reported their results, demonstrating promising efficacy against some cancers, and unique challenges. Development of the Lm-based immunotherapies continues with discovery of improved methods of attenuation, novel uses, and more effective combinatorial regimens. In this review, we provide a brief background of Listeria monocytogenes as a vaccine vector, discuss recent clinical experience with Listeria-based immunotherapies, and detail the advancements in development of improved Listeria-based vaccine platforms and in their utilization.


Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Listeria monocytogenes , Neoplasias/terapia , Animais , Vetores Genéticos , Humanos
13.
Med Sci Monit ; 27: e933088, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33994538

RESUMO

Synthetic mRNA and the expression of therapeutic proteins have accelerated vaccine development to prevent infection and heralds a new era in targeted immunotherapy in oncology. Therapeutic mRNA vaccines rely on available tumor tissue for gene sequencing analysis to compare the patient's normal cellular DNA sequences and those of the tumor. Carrier-based mRNA vaccines for cancer immunotherapy are now in development that use delivery systems based on peptides, lipids, polymers, and cationic nano-emulsions. There have also been recent developments in dendritic cell-based mRNA vaccines. For patients with available tumor tissue samples, it is possible to develop mRNA vaccines that result in the expression of tumor antigens by antigen-presenting cells (APCs), resulting in innate and adaptive immune responses. Ongoing developments in mRNA immunotherapy include modifications in the route of administration and combined delivery of multiple mRNA vaccines with checkpoint inhibitors. This Editorial aims to present a brief overview of how mRNA immunotherapy may change the therapeutic landscape of personalized medicine for patients with solid malignant tumors.


Assuntos
Vacinas Anticâncer/imunologia , Neoplasias/imunologia , Neoplasias/terapia , RNA Mensageiro/imunologia , Vacinas Sintéticas/imunologia , Humanos , Imunoterapia/métodos , Oncologia/métodos , Medicina de Precisão/métodos
14.
Int J Biol Macromol ; 183: 1891-1902, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34052270

RESUMO

Epitope peptides are not suitable for nasal administration immunity due to their poor immunogenicity and low delivery efficiency. Here, we reported an intranasal self-assembled nanovaccine (I-OVA NE), which was loaded with the peptides IKVAV-OVA257-264 (I-OVA), a laminin peptide (Ile-Lys-Val-ala-Val, IKVAV) and OVA257-264 epitope conjugated peptide. This nanovaccine with I-OVA at a concentration of 4 mg/mL showed the average particle size of 30.37 ± 2.49 nm, zeta potential of -16.67 ± 1.76 mV, and encapsulation rate of 84.07 ± 7.59%. Moreover, the mucin did not alter its stability (size, PdI and zeta potential). And it also had no obvious acute pathological changes neither in the nasal mucosa nor lung tissues after nasal administration. Meanwhile, the antigen uptake of I-OVA NE was promoted, and the nasal residence time was also prolonged in vivo. Besides, the uptake rate of this nanovaccine was obviously higher than that of free I-OVA (P < 0.001) after blocking by the integrin antibody, suggesting that the binding of IKVAV to integrin is involved in the epitope peptide uptake. Importantly, this nanovaccine enhanced peptide-specific CD8+T cells exhibiting OVA257-264-specific CTL activity and Th1 immune response, leading to the induction of the protective immunity in E.G7-OVA tumor-bearing mice. Overall, these data indicate that I-OVA NE can be an applicable strategy of tumor vaccine development.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Laminina/química , Linfoma/tratamento farmacológico , Ovalbumina/química , Fragmentos de Peptídeos/administração & dosagem , Administração Intranasal , Animais , Vacinas Anticâncer/imunologia , Linhagem Celular , Progressão da Doença , Emulsões , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfoma/imunologia , Camundongos , Nanopartículas , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Células Th1/metabolismo
15.
Food Funct ; 12(9): 4046-4059, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977945

RESUMO

Previous studies have reported that Portulaca oleracea L. polysaccharides (POL-P3b) is an immunoregulatory agent. However, few studies exist on POL-P3b as a novel immune adjuvant in combination with the DC vaccine for breast cancer treatment. In this work, a DC vaccine loaded with mouse 4T1 tumor cell antigen was prepared to evaluate the properties of POL-P3b in inducing the maturation and function of DC derived from mouse bone marrow, and then to investigate the effect of the DC vaccine combined with POL-P3b on breast cancer in vivo and in vitro. Morphological changes of DC were observed using scanning electron microscopy. Phenotypic and functional analyses of DC were detected by flow cytometry and allogeneic lymphocyte reaction. Cytokine levels in the DC culture supernatant were detected by ELISA. Western blotting analysis was used for the protein expression of TLR4, MyD88 and NF-κB. Apoptosis detection and protein expression of the tumor tissue were analyzed by TUNEL staining and immunohistochemistry, respectively. The security of POL-P3b was evaluated by the detection of hematological and blood biochemical indicators and pathological analysis for tissues. POL-P3b can induce DC activation and maturation, which is attributed to increasing the specific anti-tumor immune response, and the mechanism of action involved in the TLR4/MyD88/NF-κB signaling pathway. Experimental results in vivo further suggested that the administration of POL-P3b-treated antigen-primed DC achieved remarkable tumor growth inhibition through inducing apoptosis and enhancing immune responses. Moreover, the POL-P3b-treated DC vaccine was able to inhibit lung metastases. The results proved the feasibility of POL-P3b as an edible adjuvant of the DC vaccine for anti-breast cancer therapy.


Assuntos
Adjuvantes Imunológicos , Neoplasias da Mama/terapia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Polissacarídeos/imunologia , Portulaca/química , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/toxicidade , Animais , Antígenos de Neoplasias/imunologia , Apoptose , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Imunogenicidade da Vacina , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Polissacarídeos/toxicidade
16.
Nat Commun ; 12(1): 2626, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976179

RESUMO

By conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is currently undergoing clinical testing is a therapeutic anti-cancer vaccine that uses two different viruses expressing the same tumor antigen to prime and boost anti-tumor immunity. By providing the additional advantage of directly killing cancer cells, oncolytic viruses (OVs) constitute ideal platforms for such treatment strategy. However, given that the targeted tumor antigen is encoded into the viral genomes, its production requires robust infection and therefore, the vaccination efficiency partially depends on the unpredictable and highly variable intrinsic sensitivity of each tumor to OV infection. In this study, we demonstrate that anti-cancer vaccination using OVs (Adenovirus (Ad), Maraba virus (MRB), Vesicular stomatitis virus (VSV) and Vaccinia virus (VV)) co-administered with antigenic peptides is as efficient as antigen-engineered OVs and does not depend on viral replication. Our strategy is particularly attractive for personalized anti-cancer vaccines targeting patient-specific mutations. We suggest that the use of OVs as adjuvant platforms for therapeutic anti-cancer vaccination warrants testing for cancer treatment.


Assuntos
Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias/imunologia , Vírus Oncolíticos/genética , Poli I-C/administração & dosagem , Poli I-C/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Vírus Vaccinia , Vírus da Estomatite Vesicular Indiana , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nat Commun ; 12(1): 2935, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006895

RESUMO

With emerging supremacy, cancer immunotherapy has evolved as a promising therapeutic modality compared to conventional antitumor therapies. Cancer immunotherapy composed of biodegradable poly(lactic-co-glycolic acid) (PLGA) particles containing antigens and toll-like receptor ligands induces vigorous antitumor immune responses in vivo. Here, we demonstrate the supreme adjuvant effect of the recently developed and pharmaceutically defined double-stranded (ds)RNA adjuvant Riboxxim especially when incorporated into PLGA particles. Encapsulation of Riboxxim together with antigens potently activates murine and human dendritic cells, and elevated tumor-specific CD8+ T cell responses are superior to those obtained using classical dsRNA analogues. This PLGA particle vaccine affords primary tumor growth retardation, prevention of metastases, and prolonged survival in preclinical tumor models. Its advantageous therapeutic potency was further enhanced by immune checkpoint blockade that resulted in reinvigoration of cytotoxic T lymphocyte responses and tumor ablation. Thus, combining immune checkpoint blockade with immunotherapy based on Riboxxim-bearing PLGA particles strongly increases its efficacy.


Assuntos
Vacinas Anticâncer/imunologia , Proteína DEAD-box 58/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Imunoterapia/métodos , Neoplasias Experimentais/terapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/imunologia , Receptores Imunológicos/imunologia , Receptor 3 Toll-Like/imunologia , Animais , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral , Células Cultivadas , Proteína DEAD-box 58/metabolismo , Sinergismo Farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Ligantes , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica de Varredura , Nanopartículas/química , Nanopartículas/ultraestrutura , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Receptores Imunológicos/metabolismo , Células THP-1 , Receptor 3 Toll-Like/metabolismo , Resultado do Tratamento
18.
J Hematol Oncol ; 14(1): 71, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910591

RESUMO

BACKGROUND: CD8+ T cell-mediated adaptive cellular immunity and natural killer (NK) cell-mediated innate immunity both play important roles in tumour immunity. This study aimed to develop therapeutic tumour vaccines based on double-activation of CD8+ T and NK cells. METHODS: The immune Epitope database, Molecular Operating Environment software, and enzyme-linked immunosorbent assay were used for epitope identification. Flow cytometry, confocal microscopy, UPLC-QTOF-MS, and RNA-seq were utilized for evaluating immunity of PBMC-derived DCs, CD8+ T or NK cells and related pathways. HLA-A2.1 transgenic mice combined with immunologically reconstituted tumour-bearing mice were used to examine the antitumour effect and safety of epitope vaccines. RESULTS: We identified novel HLA-A2.1-restricted extracellular matrix protein 1(ECM1)-derived immunodominant epitopes in which LA induced a potent immune response. We also found that LA-loaded DCs upregulated the frequency of CD3+/CD8+ T cells, CD45RO+/CD69+ activated memory T cells, and CD3-/CD16+/CD56+ NK cells. We demonstrated cytotoxic granule release of LA/DC-CTLs or LA/DC-NK cells and cytotoxicity against tumour cells and microtissue blocks via the predominant IFN-γ/perforin/granzyme B cell death pathway. Further investigating the mechanism of LA-mediated CD8+ T activation, we found that LA could be internalized into DCs through phagocytosis and then formed a LA-MHC-I complex presented onto the DC surface for recognition of the T cell receptor to upregulate Zap70 phosphorylation levels to further activate CD8+ T cells by DC-CTL interactions. In addition, LA-mediated DC-NK crosstalk through stimulation of the TLR4-p38 MAPK pathway increased MICA/B expression on DCs to interact with NKG2D for NK activation. Promisingly, LA could activate CD8+ T cells and NK cells simultaneously via interacting with DCs to suppress tumours in vivo. Moreover, the safety of LA was confirmed. CONCLUSIONS: LA-induced immune antitumour activity through DC cross-activation with CD8+ T and NK cells, which demonstrated proof-of-concept evidence for the capability and safety of a novel therapeutic tumour vaccine.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Proteínas da Matriz Extracelular/imunologia , Antígeno HLA-A2/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Animais , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Humanos , Epitopos Imunodominantes/imunologia , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Neoplasias/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Arch Razi Inst ; 76(1): 1-6, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33818952

RESUMO

The Covid-19 pandemic has brought about rapid change in medical science. The production of new generation vaccines for this disease has surprised even their most optimistic supporters. Not only have these vaccines proven to be effective, but the importance of this disease and pandemic situation also significantly shortened the long-standing process of validating such products. Vaccination is a type of immunotherapy. Researchers have long been looking at vaccines as a possible treatment for cancer (Geynisman et al., 2014). In the same way that vaccines work against infectious diseases, attempts are being made to develop vaccines to identify specific proteins on cancer cells. This helps the immune system recognize and attack cancer cells. Cancer vaccines may help: I) Prevent the growth of cancer cells (Bialkowski et al., 2016), II) Prevent recurrence of cancer (Stanton and Disis, 2015), III) Destroy cancer cells left over from other treatments. The following types of cancer vaccines are being studied: Antigen Vaccines. These vaccines are made from specific proteins or antigens of cancerous cells. Their purpose is to stimulate the immune system to attack cancer cells (Tagliamonte et al., 2014). Whole-Cell Vaccines. A whole-cell vaccine uses the entire cancer cell, not just a specific molecule (antigen), to generate the vaccine. (Keenan and Jaffee, 2012).Dendritic Cell Vaccines. Dendritic cells help the immune system identify abnormal cells, such as cancerous cells. Dendritic cells are grown with cancer cells in the laboratory to produce the vaccine. The vaccine then stimulates the immune system to attack cancer. (Wang et al., 2014; Mastelic-Gavillet et al., 2019). DNA Vaccines. These vaccines are made from DNA fragments of cancer cells. They can be injected into the body to facilitate immune system cells can better respond and kill cancer cells (Gatti-Mays et al., 2017).Other Types of Cancer Vaccines. such as Anti idiotype vaccines. This vaccine stimulates the body to generate antibodies against cancerous cells. An example of an anti-idiotype antibody is Racotumomab or Vaxira (Cancer, 2016). However, conditions and considerations after Corona does not seem to be the same as before. The current pandemic situation has also led to major changes in the pharmaceutical and Vaccine production process and international protocols. Some of the most critical issues that can accelerate the introduction of cancer vaccines are: 1. Typical drug and vaccine development timeline. A typical vaccine needs 5 to 10 years and sometimes longer to design secure funding, and get approval (Figure 1). Less than 10 percent of new drugs, which are entered in the different phases of clinical trials, are advanced to approval by the Food and Drug Administration (FDA)(Cancer, 2020a). However, now the situation is not normal. Dozens of Covid 19 vaccines are starting clinical trials. Some of them use RNA and DNA technology, which delivers the body with missions to produce its antibodies against the virus. There are already at least 254 therapies and 95 vaccines related to Covid-19 being explored. However, it seems that the experiences gained in this pandemic, and advances in technology, may be effective in shortening the production path of other vaccines and drugs and the process of its approval at the national and international levels in the future. In Figure 2, the time course of production of conventional vaccines in comparison with Covid 19 vaccines (Cancer, 2020b) is shown.2. The introduction of messenger RNA (mRNA) technology into the field of prevention and treatment. Over the past decades, this technology has been considered an excellent alternative to conventional vaccination methods. Proper potency and low side effects, the possibility of fast production and relatively low production cost are its advantages. However, until recently, the instability of this molecule has been a major problem in its application. This research was started many years ago by two companies that played a significant role in developing the first Covid vaccines, so BioNTech and Moderna were able to quickly transfer their experience in the field of Covid vaccine development (Pardi et al., 2018; Moderna, 2020). Figure 3 shows how mRNA vaccines work. Bout Pfizer &ndash; BioNTech and Moderna mRNA vaccines were more than 90 % effective in preclinical stages. Millions of doses of these two vaccines are currently being injected into eligible individuals worldwide. 3. Considering the use of artificial intelligence in assessing the effectiveness of vaccines. There are always doubts about the effectiveness of the new drug in treating the disease. Once the vaccine is widely available, we will know more about its effectiveness versus it works under carefully controlled scientific testing conditions. Vaccines will continue to be monitored after use. The data collected helps professionals understand how they work in different groups of people (depending on factors such as age, ethnicity, and people with different health conditions) and also the length of protection provided by the vaccine. Artificial intelligence (AI) is an emerging field, which reaches everywhere and not only as a beneficial industrial tool but also as a practical tool in medical science and plays a crucial role in developing the computation vision, risk assessment, diagnostic, prognostic, etc. models in the field of medicine (Amisha et al., 2019). According to the wide range of AI applications in the analysis of different types of data, it can be used in vaccine production, safety assessments, clinical and preclinical studies and Covid 19 vaccines adverse reactions (CDC, 2019). Indeed, most cancer vaccines are therapeutic, rather than prophylactic, and seek to stimulate cell-mediated responses, such as those from CTLs, capable of clearing or reducing tumor burden. There are currently FDA-approved products for helping cancer treatment such as BREYANZI, TECARTUS and YESCARTA for lymphoma, IMLYGIC for melanoma, KYMRIAH for acute lymphoblastic leukemia, and PROVENGE for prostate cancer. Over the past decade, most of BioNTech&#39;s activities have been in the field of cancer vaccine design and production for melanoma (two clinical trials), breast cancer (one clinical trial), and the rest concerning viral and veterinary vaccines (two clinical trials). Also Maderno company has been working on Individualized cancer vaccines (one clinical trials), and vaccines for viral infections such as Zika and Influenza and veterinary vaccines (several clinical trials) (Pardi et al., 2018). Therefore, it can be said, mRNA technology that has been the subject of much research into the treatment of cancer has been shifted and rapidly used to produce and use the Covid 19 vaccine. The current pandemic situation has necessitated the acceleration of Covid 19 vaccines and drugs and national and international protocols for their approval. If the currently produced vaccines can continue to be as successful as the preclinical and early phase studies, these changes and evolution have raised hopes for accelerating the use of these technologies and mechanisms in the field of cancer and other diseases vaccines, including HIV and influenza.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas Anticâncer/imunologia , Neoplasias/terapia , SARS-CoV-2 , Vacinas Sintéticas/imunologia , Inteligência Artificial , Humanos , RNA Mensageiro/metabolismo
20.
Nat Rev Cancer ; 21(6): 360-378, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33907315

RESUMO

Therapeutic cancer vaccines have undergone a resurgence in the past decade. A better understanding of the breadth of tumour-associated antigens, the native immune response and development of novel technologies for antigen delivery has facilitated improved vaccine design. The goal of therapeutic cancer vaccines is to induce tumour regression, eradicate minimal residual disease, establish lasting antitumour memory and avoid non-specific or adverse reactions. However, tumour-induced immunosuppression and immunoresistance pose significant challenges to achieving this goal. In this Review, we deliberate on how to improve and expand the antigen repertoire for vaccines, consider developments in vaccine platforms and explore antigen-agnostic in situ vaccines. Furthermore, we summarize the reasons for failure of cancer vaccines in the past and provide an overview of various mechanisms of resistance posed by the tumour. Finally, we propose strategies for combining suitable vaccine platforms with novel immunomodulatory approaches and standard-of-care treatments for overcoming tumour resistance and enhancing clinical efficacy.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Tolerância Imunológica , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/prevenção & controle , Microambiente Tumoral/imunologia , Animais , Vacinas Anticâncer/imunologia , Humanos
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