RESUMO
Cancer is a major public health concern due to high mortality and poor quality of life of patients. Despite the availability of advanced therapeutic interventions, most treatment modalities are not efficacious, very expensive, and cause several adverse side effects. The factors such as drug resistance, lack of specificity, and low efficacy of the cancer drugs necessitate developing alternative strategies for the prevention and treatment of this disease. Xanthohumol (XN), a prenylated chalcone present in Hop (Humulus lupulus), has been found to possess prominent activities against aging, diabetes, inflammation, microbial infection, and cancer. Thus, this manuscript thoroughly reviews the literature on the anti-cancer properties of XN and its various molecular targets. XN was found to exert its inhibitory effect on the growth and proliferation of cancer cells via modulation of multiple signaling pathways such as Akt, AMPK, ERK, IGFBP2, NF-κB, and STAT3, and also modulates various proteins such as Notch1, caspases, MMPs, Bcl-2, cyclin D1, oxidative stress markers, tumor-suppressor proteins, and miRNAs. Thus, these reports suggest that XN possesses enormous therapeutic potential against various cancers and could be potentially used as a multi-targeted anti-cancer agent with minimal adverse effects.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Neoplasias/tratamento farmacológico , Propiofenonas/química , Propiofenonas/farmacologia , Bibliometria , Feminino , Flavonoides/farmacocinética , Humanos , Humulus/química , Masculino , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Propiofenonas/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Lung cancer represents one of the most prevalent neoplasms across the globe. Tobacco smoking, exposure to different occupational and environmental carcinogens, and various dietary factors are strongly implicated in the development of lung cancer. The 5-year survival rate of lung cancer is extremely poor which can be attributed to its propensity for early spread, lack of appropriate biomarkers and proper therapeutic strategies for this aggressive neoplasm. Emerging evidence suggests tumor necrosis factor-α-induced protein eight like 1 (TIPE1 or TNFAIP8L1), which functions as a cell death regulator, to hold high prospect as an important biomarker. Interestingly, this protein was found to be significantly downregulated in human lung cancer tissues compared to normal lung tissues. In addition, this protein exerted marked downregulation in different stages and grades of lung tumor. Further knockout of TIPE1 led to the enhancement in proliferation, survival, migration and invasion of NCIH460 human lung cancer cells through modulation of Akt/mTOR/STAT-3 signaling cascade. In addition, TIPE1 was found to be involved in nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N-nitrosonornicotine and benzo[a]pyrene-mediated lung cancer through enhanced proliferation, survival and migration of lung cancer cells. Altogether, this newly identified protein plays a critical role in lung cancer pathogenesis and possess enormous prospect to serve as an important tool in the effective management of this aggressive neoplasm.
Assuntos
Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/patologia , Apoptose , Biomarcadores Tumorais/genética , Sistemas CRISPR-Cas , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Invasividade Neoplásica , Prognóstico , Células Tumorais CultivadasRESUMO
In spite of billions of dollars expended on cancer research every year, the incidence rate and the mortality rate due to this widespread disease has increased drastically over the last few decades. Recent reports from the World Health Organization advocate that overall global cancer burden and deaths due to cancer are expected to double by the next decade. Synthetic drugs developed as chemotherapeutics have repeatedly shown adverse side effects and development of chemoresistance. Cancer is basically a multifactorial disease that necessitates the modulation of multiple targets and oncogenic signaling pathways. Honokiol (C18H18O2) is a biphenolic natural compound isolated from the leaves and barks of Magnolia plant species and has been extensively studied for its beneficial effects against several chronic diseases. Honokiol is capable of efficiently preventing the growth of wide variety of tumors such as those of brain, breast, cervical, colon, liver, lung, prostate, skin, and hematological malignancies. Recent work has shown that this phytochemical can modulate various molecular targets such as activation of pro-apoptotic factors, suppression of anti-apoptotic proteins and different transcription factors, downregulation of various enzymes, chemokines, cell surface adhesion molecules, and cell cycle proteins, and inhibition of activity of protein tyrosine kinases and serine/threonine kinases. Because of its pharmacological safety, honokiol can either be used alone or in combination with other chemotherapeutic drugs for the prevention and treatment of cancer. The current review describes in detail the various reports supporting these anti-cancer studies documented with this promising agent.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Lignanas/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Humanos , Lignanas/química , Lignanas/farmacologia , Magnolia/química , Terapia de Alvo Molecular , Neoplasias/prevenção & controleRESUMO
Natural compounds, in recent years, have attracted significant attention for their use in the prevention and treatment of diverse chronic diseases as they are devoid of major toxicities. Boswellic acid (BA), a series of pentacyclic triterpene molecules, is isolated from the gum resin of Boswellia serrata and Boswellia carteri. It proved to be one such agent that has exhibited efficacy against various chronic diseases like arthritis, diabetes, asthma, cancer, inflammatory bowel disease, Parkinson's disease, Alzheimer's, etc. The molecular targets attributed to its wide range of biological activities include transcription factors, kinases, enzymes, receptors, growth factors, etc. The present review is an attempt to demonstrate the diverse pharmacological uses of BA, along with its underlying molecular mechanism of action against different ailments. Further, this review also discusses the roadblocks associated with the pharmacokinetics and bioavailability of this promising compound and strategies to overcome those limitations for developing it as an effective drug for the clinical management of chronic diseases.
Assuntos
Triterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Doença Crônica/tratamento farmacológico , Humanos , Camundongos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologia , Relação Estrutura-Atividade , Triterpenos/administração & dosagem , Triterpenos/química , Triterpenos/farmacocinéticaRESUMO
Despite the significant advancements in the diagnosis and treatment of cancer, it still remains one of the most fatal diseases in the world due to the lack of sensitive diagnosis methods and effective drugs. Therefore, discovering novel therapies that are safe, efficacious and affordable are required for the better management of this disease. Tocotrienols, analogues of vitamin E have gained increased attention due to their safety and efficacy. Extensive research over the past several years has strongly indicated that tocotrienols can efficiently prevent/inhibit the growth of different cancers such as cancers of blood, brain, breast, cervical, colon, liver, lung, pancreas, prostate, skin, stomach etc. This is mainly accredited to their ability to modulate various molecular targets involved in cancer cell proliferation, survival, invasion, angiogenesis, and metastasis such as NF-κB, STAT3, Akt/mTOR, etc. In addition, increasing lines of evidence has shown that tocotrienols can sensitize cancer cells to chemotherapeutic agents such as celecoxib, doxorubicin, erlotinib, gefitinib, gemcitabine, paclitaxel, statin etc. Moreover, several clinical trials have confirmed the safety and tolerability of tocotrienols in humans. This review summarizes the potential of tocotrienols for the prevention and treatment of different cancers based on the available in vitro, in vivo and clinical studies.
Assuntos
Antioxidantes/uso terapêutico , Neoplasias/tratamento farmacológico , Tocotrienóis/uso terapêutico , Vitaminas/uso terapêutico , Animais , Quimioprevenção , Humanos , Neoplasias/metabolismo , Neoplasias/prevenção & controleRESUMO
The intake of fruits has proven to reduce the risk and incidence of cancer worldwide and plays a crucial role in cancer prevention. Pomegranate (Punica granatum), which belongs to the Punicaceae family, is one such plant that contains beneficial nutrients as well as many bioactive components and important phytochemicals that can be attributed to cancer-related therapeutic purposes. Pomegranate possesses antioxidant, anti-inflammatory, anti-proliferative, anti-angiogenic, anti-invasive, and anti-metastatic properties, and induces apoptosis. It also down-regulates various signaling pathways such as NF-κB, PI3K/AKT/mTOR, and Wnt, and down-regulates the expression of genes that are responsible in cancer development, such as anti-apoptotic genes, MMPs, VEGF, c-met, cyclins, Cdks, and pro-inflammatory cytokines. Therefore, inclusion of the fruit in one's diet would assist in a healthy life protected from cancer and also act as an effective chemotherapeutic with no toxic side effects.
Assuntos
Antineoplásicos/uso terapêutico , Lythraceae , Neoplasias/tratamento farmacológico , Fitoterapia , Preparações de Plantas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Humanos , Preparações de Plantas/farmacologiaRESUMO
The tumor necrosis factor-α-induced protein 8-like (TIPE/TNFAIP8) family is a recently identified family of proteins that is strongly associated with the regulation of immunity and tumorigenesis. This family is comprised of four members, namely, tumor necrosis factor-α-induced protein 8 (TIPE/TNFAIP8), tumor necrosis factor-α-induced protein 8-like 1 (TIPE1/TNFAIP8L1), tumor necrosis factor-α-induced protein 8-like 2 (TIPE2/TNFAIP8L2), and tumor necrosis factor-α-induced protein 8-like 3 (TIPE3/TNFAIP8L3). Although the proteins of this family were initially described as regulators of tumorigenesis, inflammation, and cell death, they are also found to be involved in the regulation of autophagy and the transfer of lipid secondary messengers, besides contributing to immune function and homeostasis. Interestingly, despite the existence of a significant sequence homology among the four members of this family, they are involved in different biological activities and also exhibit remarkable variability of expression. Furthermore, this family of proteins is highly deregulated in different human cancers and various chronic diseases. This review summarizes the vivid role of the TIPE family of proteins and its association with various signaling cascades in diverse chronic diseases.
Assuntos
Doença Crônica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias/metabolismoRESUMO
Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings.
Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Curcumina/uso terapêutico , Receptores ErbB/fisiologia , Humanos , NF-kappa B/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Fator de Transcrição STAT3/fisiologiaRESUMO
BACKGROUND: Advanced clear cell renal cell carcinoma (ccRCC) is a prevalent kidney cancer for which long-term survival rates are abysmal, though immunotherapies are showing potential. Not yet clinically vetted are bispecific T cell engagers (BTEs) that activate T cell-mediated cancer killing through intercellular synapsing. Multiple BTE formats exist, however, with limited cross-characterizations to help optimize new drug design. Here, we developed BTEs to treat ccRCC by targeting carbonic anhydrase 9 (CA9) while characterizing the persistent BTE (PBTE) format and comparing it to a new format, the persistent multivalent T cell engager (PMTE). These antibody therapies against ccRCC are developed as both recombinant and synthetic DNA (synDNA) medicines. METHODS: Antibody formatting effects on binding kinetics were assessed by flow cytometry and intercellular synaptic strength assays while potency was tested using T-cell activation and cytotoxicity assays. Mouse models were used to study antibody plasma and tumor pharmacokinetics, as well as antitumor efficacy as both recombinant and synDNA medicines. Specifically, three models using ccRCC cell line xenografts and human donor T cells in immunodeficient mice were used to support this study. RESULTS: Compared with a first-generation BTE, we show that the PBTE reduced avidity, intercellular synaptic strength, cytotoxic potency by as much as 33-fold, and ultimately efficacy against ccRCC tumors in vivo. However, compared with the PBTE, we demonstrate that the PMTE improved cell avidity, restored intercellular synapses, augmented cytotoxic potency by 40-fold, improved tumor distribution pharmacokinetics by 2-fold, and recovered synDNA efficacy in mouse tumor models by 20-fold. All the while, the PMTE displayed a desirable half-life of 4 days in mice compared with the conventional BTE's 2 hours. CONCLUSIONS: With impressive efficacy, the CA9-targeted PMTE is a promising new therapy for advanced ccRCC, which can be effectively delivered through synDNA. The highly potent PMTE format itself is a promising new tool for future applications in the multispecific antibody space.
Assuntos
Anticorpos Biespecíficos , Carcinoma de Células Renais , Neoplasias Renais , Linfócitos T , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Humanos , Animais , Camundongos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/imunologia , Linfócitos T/imunologia , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Linhagem Celular Tumoral , Imunoterapia/métodos , Anidrase Carbônica IX/metabolismo , Feminino , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glioblastoma multiforme (GBM) is among the most difficult cancers to treat with a 5-year survival rate less than 5%. An immunotherapeutic vaccine approach targeting GBM-specific antigen, EGFRvIII, previously demonstrated important clinical impact. However, immune escape variants were reported in the trial, suggesting that multivalent approaches targeting GBM-associated antigens may be of importance. Here we focused on multivalent in vivo delivery of synthetic DNA-encoded bispecific T cell engagers (DBTEs) targeting two GBM-associated antigens, EGFRvIII and HER2. We designed and optimized an EGFRvIII-DBTE that induced T cell-mediated cytotoxicity against EGFRvIII-expressing tumor cells. In vivo delivery in a single administration of EGFRvIII-DBTE resulted in durable expression over several months in NSG mice and potent tumor control and clearance in both peripheral and orthotopic animal models of GBM. Next, we combined delivery of EGFRvIII-DBTEs with an HER2-targeting DBTE to treat heterogeneous GBM tumors. In vivo delivery of dual DBTEs targeting these two GBM-associated antigens exhibited enhanced tumor control and clearance in a heterogeneous orthotopic GBM challenge, while treatment with single-target DBTE ultimately allowed for tumor escape. These studies support that combined delivery of DBTEs, targeting both EGFRvIII and HER2, can potentially improve outcomes of GBM immunotherapy, and such multivalent approaches deserve additional study.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear. We found that NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2 antigen-expressing cells (in direct cytolytic and antibody-dependent cell cytotoxicity [ADCC] assays) than NK cells from mild COVID-19 patients or negative controls. The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen. Phenotypic and functional analyses showed that NK cells expressing the glyco-immune checkpoint Siglec-9 elicited higher ADCC than Siglec-9- NK cells. Consistently, Siglec-9+ NK cells exhibit an activated and mature phenotype with higher expression of CD16 (FcγRIII; mediator of ADCC), CD57 (maturation marker), and NKG2C (activating receptor), along with lower expression of the inhibitory receptor NKG2A, than Siglec-9- CD56dim NK cells. These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other viral infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells. These data support a model in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while it is restrained by the inhibitory effects of Siglec-9. Alleviating the Siglec-9-mediated restriction on NK cytotoxicity may further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. IMPORTANCE One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity. Several viruses, such as hepatitis B virus (HBV) and HIV, also use a similar mechanism to evade NK surveillance. We found that NK cells from SARS-CoV-2-hospitalized patients are less able to function against cells expressing SARS-CoV-2 Spike protein than NK cells from SARS-CoV-2 mild patients or uninfected controls. We also found that the cytotoxicity of the Siglec-9+ NK subpopulation is indeed restrained by the inhibitory nature of the Siglec-9 molecule and that blocking Siglec-9 can enhance the ability of NK cells to target cells expressing SARS-CoV-2 antigens. Our results suggest that a targetable glyco-immune checkpoint mechanism, Siglec-9/sialoglycan interaction, may contribute to the ability of SARS-CoV-2 to evade NK immune surveillance.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Anticorpos/metabolismo , Citotoxicidade Celular Dependente de Anticorpos , COVID-19/metabolismo , Células Matadoras Naturais , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismoRESUMO
Ovarian cancer (OC) is a lethal gynecologic malignancy, with modest responses to CPI. Engagement of additional immune arms, such as NK cells, may be of value. We focused on Siglec-7 as a surface antigen for engaging this population. Human antibodies against Siglec-7 were developed and characterized. Coculture of OC cells with PBMCs/NKs and Siglec-7 binding antibodies showed NK-mediated killing of OC lines. Anti-Siglec-7 mAb (DB7.2) enhanced survival in OC-challenged mice. In addition, the combination of DB7.2 and anti-PD-1 demonstrated further improved OC killing in vitro. To use Siglec-7 engagement as an OC-specific strategy, we engineered an NK cell engager (NKCE) to simultaneously engage NK cells through Siglec-7, and OC targets through FSHR. The NKCE demonstrated robust in vitro killing of FSHR+ OC, controlled tumors, and improved survival in OC-challenged mice. These studies support additional investigation of the Siglec-7 targeting approaches as important tools for OC and other recalcitrant cancers.
Assuntos
Produtos Biológicos , Neoplasias Ovarianas , Feminino , Humanos , Camundongos , Animais , Produtos Biológicos/metabolismo , Células Matadoras Naturais , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/metabolismo , Antígenos CD/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismoRESUMO
Despite advances in ovarian cancer (OC) therapy, recurrent OC remains a poor-prognosis disease. Because of the close interaction between OC cells and the tumor microenvironment (TME), it is important to develop strategies that target tumor cells and engage components of the TME. A major obstacle in the development of OC therapies is the identification of targets with expression limited to tumor surface to avoid off-target interactions. The follicle-stimulating hormone receptor (FSHR) has selective expression on ovarian granulosa cells and is expressed on 50%-70% of serous OCs. We generated mAbs targeting the external domain of FSHR using in vivo-expressed FSHR vector. By high-throughput flow analysis, we identified multiple clones and downselected D2AP11, a potent FSHR surface-targeted mAb. D2AP11 identifies important OC cell lines derived from tumors with different mutations, including BRCA1/2, and lines resistant to a wide range of therapies. We used D2AP11 to develop a bispecific T cell engager. In vitro addition of PBMCs and T cells to D2AP11-TCE induced specific and potent killing of different genetic and immune escape OC lines, with EC50s in the ng/ml range, and attenuated tumor burden in OC-challenged mouse models. These studies demonstrate the potential utility of biologics targeting FSHR for OC and perhaps other FSHR-positive cancers.
Assuntos
Neoplasias Ovarianas , Receptores do FSH , Humanos , Animais , Camundongos , Feminino , Receptores do FSH/genética , Receptores do FSH/metabolismo , Recidiva Local de Neoplasia , Imunoterapia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/patologia , Anticorpos Monoclonais/uso terapêutico , Imunidade Adaptativa , Microambiente TumoralRESUMO
Lung cancer is the foremost cause of cancer related mortality among men and one of the most fatal cancers among women. Notably, the 5-year survival rate of lung cancer is very low; 5% in developing countries. This low survival rate can be attributed to factors like late stage diagnosis, rapid postoperative recurrences in the patients undergoing treatment and development of chemoresistance against different agents used for treating lung cancer. Therefore, in this study we evaluated the potential of a recently identified protein namely TIPE3 which is known as a transfer protein of lipid second messengers as a lung cancer biomarker. TIPE3 was found to be significantly upregulated in lung cancer tissues indicating its role in the positive regulation of lung cancer. Supporting this finding, knockout of TIPE3 was also found to reduce the proliferation, survival and migration of lung cancer cells and arrested the G2 phase of cell cycle through inactivation of Akt/mTOR, NF-κB, STAT-3 signaling. It is well evinced that tobacco is the major risk factor of lung cancer which affects both males and females. Therefore, this study also evaluated the involvement of TIPE3 in tobacco mediated lung carcinogenesis. Notably, this study shows for the first time that TIPE3 positively regulates tobacco induced proliferation, survival and migration of lung cancer through modulation of Akt/mTOR signaling. Thus, TIPE3 plays critical role in the pathogenesis of lung cancer and hence it can be specifically targeted to develop novel therapeutic strategies.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Biomarcadores Tumorais/deficiência , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Técnicas de Inativação de Genes/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neoplasias Pulmonares/patologia , NF-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
Vaccines are one of mankind's greatest medical advances, and their use has drastically reduced and in some cases eliminated (e.g., smallpox) disease and death caused by infectious agents. Traditional vaccine modalities including live-attenuated pathogen vaccines, wholly inactivated pathogen vaccines, and protein-based pathogen subunit vaccines have successfully been used to create efficacious vaccines against measles, mumps, rubella, polio, and yellow fever. These traditional vaccine modalities, however, take many months to years to develop and have thus proven less effective for use in creating vaccines to emerging or reemerging infectious diseases (EIDs) including influenza, Human immunodeficiency virus (HIV), dengue virus (DENV), chikungunya virus (CHIKV), West Nile virus (WNV), Middle East respiratory syndrome (MERS), and the severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV and SARS-CoV-2). As factors such as climate change and increased globalization continue to increase the pace of EID development, newer vaccine modalities are required to develop vaccines that can prevent or attenuate EID outbreaks throughout the world. One such modality, DNA vaccines, has been studied for over 30 years and has numerous qualities that make them ideal for meeting the challenge of EIDs including; (1) DNA vaccine candidates can be designed within hours of publishing of a pathogens genetic sequence; (2) they can be manufactured cheaply and rapidly in large quantities; (3) they are thermostable and have reduced requirement for a cold-chain during distribution, and (4) they have a remarkable safety record in the clinic. Optimizations made in plasmid design as well as in DNA vaccine delivery have greatly improved the immunogenicity of these vaccines. Here we describe the process of making a DNA vaccine to an EID pathogen and describe methods used for assessing the immunogenicity and protective efficacy of DNA vaccines in small animal models.
Assuntos
Doenças Transmissíveis Emergentes , Vacinas de DNA , Vacinas Virais , Animais , COVID-19 , Doenças Transmissíveis Emergentes/prevenção & controle , Humanos , Imunidade , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , SARS-CoV-2 , Vacinas Atenuadas/imunologia , Vacinas de DNA/imunologia , Vacinas de Produtos Inativados/imunologia , Vacinas Sintéticas/imunologia , Vacinas Virais/genética , Vacinas Virais/imunologiaRESUMO
Glioblastoma is an aggressive tumor with poor survival rates. Bispecific T cell engagers (BTEs) against different cancers are in various stages of clinical development. Toxicity resulting from cytokine release syndrome and the short half-life of BTEs, which necessitates continuous infusion, complicating delivery and increasing costs, are major challenges in the field. Here we describe the development of in vivo DNA-launched BTEs (dBTEs) with highly focused targeting of interleukin-13 receptor α2 (IL-13Rα2), a glioblastoma cell-surface target. We developed 4 BTEs targeting 2 epitopes of IL-13Rα2 and studied how heavy-light chain orientation affects BTE function. The dBTEs induced T cell activation, cytokine production, and tumor cytolysis in the presence of IL-13Rα2+ tumor cells, but we observed unique patterns of immune activation. We found a strong correlation between granzyme B secretion and dBTE-induced cytolysis of specific and nonspecific tumors. We down-selected dBTE PB01-forward based on lower cytokine induction profile and highest activation specificity. In vivo, dBTE PB01-forward demonstrated an improved half-life versus intravenous recombinant BTE delivery. In an orthotopic glioblastoma model, dBTE PB01-forward controlled tumor growth, improving animal survival, supporting the hypothesis that the blood-brain barrier does not affect the function of systemically delivered dBTE. Further study of PB01-forward for targeting glioblastoma and other IL-13Rα2+ cancers is warranted.
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Latent Epstein-Barr virus (EBV) infection is associated with several types of cancer. Several clinical studies have targeted EBV antigens as immune therapeutic targets with limited efficacy of EBV malignancies, suggesting that additional targets might be important. BamHI-A rightward frame 1 (BARF1) is an EBV antigen that is highly expressed in EBV+ nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC). BARF1 antigen can transform human epithelial cells in vivo. BARF1-specific antibodies and cytotoxic T cells were detected in some EBV+ NPC patients. However, BARF1 has not been evaluated as an antigen in the context of therapeutic immunization. Its possible importance in this context is unclear. Here, we developed a synthetic-DNA-based expression cassette as immunotherapy targeting BARF1 (pBARF1). Immunization with pBARF1 induced potent antigen-specific humoral and T cell responses in vivo. Immunization with pBARF1 plasmid impacted tumor progression through the induction of CD8+ T cells in novel BARF1+ carcinoma models. Using an in vivo imaging system, we observed that pBARF1-immunized animals rapidly cleared cancer cells. We demonstrated that pBARF1 can induce antigen-specific immune responses that can impact cancer progression. Further study of this immune target is likely important as part of therapeutic approaches for EBV+ malignancies.
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A new pandemic is ongoing in several parts of the world. The agent responsible is the newly emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The symptoms associated with this virus are known as the coronavirus disease-2019 (COVID-19). In this review, we summarize the published data on virus specific antibodies in hospitalized patients with COVID-19 disease, patients recovered from the disease and the individuals who are asymptomatic with SARS-CoV-2 infections. The review highlights the following: i) an adjunct role of antibody tests in the diagnosis of COVID-19 in combination with RT-PCR; ii) status of antibodies from COVID-19 convalescent patients to select donors for plasma therapy; iii) the potential confounding effects of other coronaviruses, measles, mumps and rubella in antibody testing due to homology of certain viral genes; and iv) the role of antibody testing for conducting surveillance in populations, incidence estimation, contact tracing and epidemiologic studies.
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Sialic acid-binding Immunoglobulin-like lectin-9 (Siglec-9) is a glyco-immune negative checkpoint expressed on several immune cells. Siglec-9 exerts its inhibitory effects by binding to sialoglycan ligands expressed on cancer cells, enabling them to evade immunosurveillance. We developed a panel of human anti-Siglec-9 hybridoma clones by immunizing mice with Siglec-9-encoding DNA and Siglec-9 protein. The lead antibodies, with high specificity and functionality against Siglec-9, were identified through screening of clones. The in vitro cytotoxicity assays showed that our lead antibody enhances anti-tumor immune activity. Further, in vivo testing utilizing ovarian cancer humanized mouse model showed a drastic reduction in tumor volume. Together, we developed novel antibodies that augment anti-tumor immunity through interference with Siglec-9-mediated immunosuppression.
RESUMO
Prostate cancer is a prevalent cancer in men and consists of both indolent and aggressive phenotypes. While active surveillance is recommended for the former, current treatments for the latter include surgery, radiation, chemo and hormonal therapy. It has been observed that the recurrence in the treated patients is high and results in castration resistant prostate cancer for which treatment options are limited. This scenario has prompted us to consider immunotherapy with synthetic DNA vaccines, as this approach can generate antigen-specific tumor-killing immune cells. Given the multifocal and heterogeneous nature of prostate cancer, we hypothesized that synthetic DNA vaccines targeting different prostate specific antigens are likely to induce broader and improved immunity who are at high risk as well as advanced clinical stage of prostate cancer, compared to a single antigen approach. Utilizing a bioinformatics approach, synthetic enhanced DNA vaccine (SEV) constructs were generated against STEAP1, PAP, PARM1, PSCA, PCTA and PSP94. Synthetic enhanced vaccines for prostate cancer antigens were shown to elicit antigen-specific immune responses in mice and the anti-tumor activity was evident in a prostate tumor challenge mouse model. These studies support further evaluation of the DNA tools for immunotherapy of prostate cancer and perhaps other cancers.