RESUMO
Recent advances in biomolecular engineering have led to novel cancer immunotherapies with sophisticated programmed functions, including chimeric antigen receptor (CAR) T cells that bind tumor-associated antigens (TAA) to direct coordinated immune responses. Extensive engineering efforts have been made to program not only CAR specificity, but also downstream pathways that activate molecular responses. Collectively, these efforts can be conceptualized as an immunotherapy circuit: TAAs bind the CAR as input signals; intracellular signaling cascades process the binding interactions into transcriptional and translational events; and those events program effector output functions. More simply, this sequence may be abstracted as input, processing, and output. In this review, we discuss the increasingly complex scene of synthetic-biology solutions in cancer immunotherapy and summarize recent work within the framework of immunotherapy circuits. In doing so, a toolbox of basic modular circuits may be established as a foundation upon which sophisticated solutions can be constructed to meet more complex problems.See related article on p. 5.
Assuntos
Imunoterapia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Humanos , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Biologia Sintética/tendências , Linfócitos T/imunologiaRESUMO
This study aims to enhance efficacy and reduce toxicity of the combination treatment of a drug and curcumin (Cur) on leukemic stem cell and leukemic cell lines, including KG-1a and KG-1 (FLT3+ LSCs), EoL-1 (FLT3+ LCs), and U937 (FLT3- LCs). The cytotoxicity of co-treatments of doxorubicin (Dox) or idarubicin (Ida) at concentrations of the IC10-IC80 values and each concentration of Cur at the IC20, IC30, IC40, and IC50 values (conditions 1, 2, 3, and 4) was determined by MTT assays. Dox-Cur increased cytotoxicity in leukemic cells. Dox-Cur co-treatment showed additive and synergistic effects in several conditions. The effect of this co-treatment on FLT3 expression in KG-1a, KG-1, and EoL-1 cells was examined by Western blotting. Dox-Cur decreased FLT3 protein levels and total cell numbers in all the cell lines in a dose-dependent manner. In summary, this study exhibits a novel report of Dox-Cur co-treatment in both enhancing cytotoxicity of Dox and inhibiting cell proliferation via FLT3 protein expression in leukemia stem cells and leukemic cells. This is the option of leukemia treatment with reducing side effects of chemotherapeutic drugs to leukemia patients.
Assuntos
Curcumina/farmacologia , Doxorrubicina/farmacologia , Idarubicina/farmacologia , Leucemia Mieloide Aguda/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/metabolismo , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcuma/química , Proteínas do Citoesqueleto/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Rizoma/químicaRESUMO
Absolute quantification measurements (copies per cell) of peptide major histocompatibility complex (pMHC) antigens are necessary to inform targeted immunotherapy drug design; however, existing methods for absolute quantification have critical limitations. Here, we present a platform termed SureQuant-IsoMHC, utilizing a series of pMHC isotopologues and internal standard-triggered targeted mass spectrometry to generate an embedded multipoint calibration curve to determine endogenous pMHC concentrations for a panel of 18 tumor antigens. We apply SureQuant-IsoMHC to measure changes in expression of our target panel in a melanoma cell line treated with a MEK inhibitor and translate this approach to estimate antigen concentrations in melanoma tumor biopsies.
Assuntos
Apresentação de Antígeno/imunologia , Antígenos de Neoplasias/análise , Benzimidazóis/farmacologia , Antígenos de Histocompatibilidade Classe I/imunologia , MAP Quinase Quinase 1/antagonistas & inibidores , Melanoma/imunologia , Apresentação de Antígeno/efeitos dos fármacos , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunoterapia , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Células Tumorais CultivadasRESUMO
Although immune-checkpoint inhibitors (ICIs) have been a remarkable advancement in bladder cancer treatment, the response rate to single-agent ICIs remains suboptimal. There has been substantial interest in the use of epigenetic agents to enhance ICI efficacy, although precisely how these agents potentiate ICI response has not been fully elucidated. We identified entinostat, a selective HDAC1/3 inhibitor, as a potent antitumor agent in our immune-competent bladder cancer mouse models (BBN963 and BBN966). We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment, resulting in a robust antitumor response that was cell autonomous, dependent upon antigen presentation, and associated with increased numbers of neoantigen-specific T cells. Finally, combination treatment with anti-PD-1 and entinostat led to complete responses and conferred long-term immunologic memory. Our work defines a tumor cell-autonomous mechanism of action for entinostat and a strong preclinical rationale for the combined use of entinostat and PD-1 blockade in bladder cancer.
Assuntos
Antígenos de Neoplasias/efeitos dos fármacos , Benzamidas/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Piridinas/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Humanos , Imunidade/efeitos dos fármacos , Imunocompetência/efeitos dos fármacos , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Linfócitos T/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologiaRESUMO
OBJECTIVE: To evaluate the predictive value of a single nucleotide polymorphism (SNP) rs2686344 and squamous cell carcinoma antigen (SCCAg) levels in the clinical efficacy of neoadjuvant chemotherapy (NACT) for cervical cancer. METHODS: A total of 92 patients with stage IB2-IIIB carcinoma of the uterine cervix who received NACT treatment were enrolled. The relationship between the genotypes of SNP rs2686344 which is located on CAMKK2 on chromosome 12, SCCAg levels and the response to NACT was analyzed. The relationship between the SNP rs2686344 genotypes, SCCAg levels, the response to NACT and the five-year survival rate was evaluated. RESULTS: The effective group accounted for 84.85% in patients with low level (≤3.5 ng/mL) of post-treatment SCCAg (post-SCCAg), while the ineffective group accounted for 15.15%. The post-SCCAg levels and the genotypes of rs2686344 were significantly correlated with NACT response (Pâ¯=â¯0.003, and Pâ¯=â¯0.006). In patients with CC or CT genotype of SNP rs2686344, effective group accounted for 81.18%, while ineffective group accounted for 18.82%; For patients with TT genotype, effective response group accounted for 28.57%, ineffective group accounted for 71.43%. Post-SCCAg level >3.5 ng/mL and TT genotype of SNP rs2686344 showed as independent risk factors for NACT response in the multivariate analysis (Pâ¯=â¯0.002, and Pâ¯=â¯0.048). There was no significant difference in 5-year overall survival and 5-year disease-free survival between patients with different levels of post-SCCAg, or among different rs2686344 genotypes. CONCLUSION: The high level of post-SCCAg (>3.5 ng/mL) and TT genotype of rs2686344 may suggest a higher risk of poor response to NACT.
Assuntos
Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/genética , Serpinas/efeitos dos fármacos , Serpinas/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Biomarcadores Tumorais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , China/epidemiologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Taxa de Sobrevida , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologiaRESUMO
Ovarian cancer is one of the highly prominent gynecological malignancies after breast cancer. Although myriad literature is available, there is no specific biomarker available for the personalized treatment strategy. The unavailability of effective drug therapy for ovarian cancer calls for an urgent push in its development from the multidisciplinary scientific community. Indian Ayurvedic medicine pharmacology is widely appreciated and accepted for its immense healthcare benefits. Bioinformatics and cheminformatics approaches can be effectively used to screen phytochemicals present in the Indian Ayurvedic plants against ovarian cancer target receptors. Recent studies discern that POTE, a cancer-testis antigen (CTA) family, plays a crucial role in the proliferation and progression of cancers including ovarian cancer. Specifically, POTEE paralog has been observed to be hypermethylated in ovarian cancer. This study undertakes an in silico analysis of Indian Ayurvedic plants for their anticancer efficacy against ovarian cancer proliferation target receptor POTEE. Structures of 100 phytochemicals from 11 Ayurvedic plants were screened with ADME criteria, and qualified phytochemicals were subjected to molecular docking and interaction analysis. Only 6 phytochemicals having a high affinity to the target receptor (POTEE) were then subjected to an all-atom replica exchange molecular dynamics simulation for 50 ns. Binding affinities of 6 phytochemicals cedeodarin, deodarin, hematoxylin, matairesinol, quercetin, and taxifolin with POTEE were -8.1, -7.7, -7.7, -7.9, -8.0, and - 7.7 kcal/mol, respectively, and their RMSD were recorded as zero. This study concludes that phytochemicals present in Indian Ayurvedic plants namely Cedrus deodara and Asparagus racemosus possess inhibitory effects against ovarian cancer proliferation receptor POTEE.
Assuntos
Antígenos de Neoplasias/efeitos dos fármacos , Ayurveda , Simulação de Acoplamento Molecular , Neoplasias Ovarianas/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Antígenos de Neoplasias/química , Proliferação de Células , Feminino , Furanos/química , Furanos/farmacologia , Hematoxilina/química , Hematoxilina/farmacologia , Humanos , Lignanas/química , Lignanas/farmacologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/fisiopatologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/uso terapêutico , Quercetina/análogos & derivados , Quercetina/química , Quercetina/farmacologiaRESUMO
The engineering of T cells through expression of chimeric antigen receptors (CARs) against tumor-associated antigens (TAAs) has shown significant potential for use as an anti-cancer therapeutic. The development of strategies for flexible and modular CAR T systems is accelerating, allowing for multiple antigen targeting, precise programming, and adaptable solutions in the field of cellular immunotherapy. Moving beyond the fixed antigen specificity of traditional CAR T systems, the modular CAR T technology splits the T cell signaling domains and the targeting elements through use of a switch molecule. The activity of CAR T cells depends on the presence of the switch, offering dose-titratable response and precise control over CAR T cells. In this review, we summarize developments in universal or modular CAR T strategies that expand on current CAR T systems and open the door for more customizable T cell activity.
Assuntos
Imunoterapia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Engenharia Celular/tendências , Humanos , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologiaRESUMO
The advent of immunotherapy has revolutionized cancer treatment. Prostate cancer has an immunosuppressive microenvironment and a low tumor mutation burden, resulting in low neoantigen expression. The consensus was that immunotherapy would be less effective in prostate cancer. However, recent studies have reported that prostate cancer does have a high number of DNA damage and repair gene defects. Immunotherapies that have been tested in prostate cancer so far have been mainly vaccines and checkpoint inhibitors. A combination of genomically targeted therapies, with approaches to alleviate immune response and thereby make the tumor microenvironment immunologically hot, is promising.
Assuntos
Produtos Biológicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Microambiente Tumoral/efeitos dos fármacos , Idoso , Animais , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Previsões , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , Estadiamento de Neoplasias , Neoplasias da Próstata/genética , Resultado do Tratamento , Microambiente Tumoral/genéticaRESUMO
PURPOSE: Bispecific antibodies (BsAbs) have emerged as a leading drug class for cancer therapy and are becoming increasingly of interest for therapeutic applications. As of April 2020, over 123 BsAbs are under clinical evaluation for use in oncology (including the two marketed BsAbs Blinatumomab and Catumaxomab). The majority (82 of 123) of BsAbs under clinical evaluation can be categorized as bispecific immune cell engager whereas a second less well-discussed subclass of BsAbs targets two tumor-associated antigens (TAAs). In this review, we summarize the clinical development of dual TAAs targeting BsAbs and provide an overview of critical considerations when designing dual TAA targeting BsAbs. METHODS: Herein the relevant literature and clinical trials published in English until April 1st 2020 were searched using PubMed and ClinicalTrials.gov database. BsAbs were considered to be active in clinic if their clinical trials were not terminated, withdrawn or completed before 2018 without reporting results. Data missed by searching ClinicalTrials.gov was manually curated. RESULTS: Dual TAAs targeting BsAbs offer several advantages including increased tumor selectivity, potential to concurrently modulate two functional pathways in the tumor cell and may yield improved payload delivery. CONCLUSIONS: Dual TAAs targeting BsAbs represent a valuable class of biologics and early stage clinical studies have demonstrated promising anti-tumor efficacy in both hematologic malignancies and solid tumors.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos de Neoplasias/imunologia , Neoplasias/terapia , Anticorpos Biespecíficos/imunologia , Antígenos de Neoplasias/efeitos dos fármacos , Humanos , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
INTRODUCTION AND OBJECTIVE: Non-alcoholic fatty liver disease remains as one of the main liver disorders worldwide. It is widely accepted that is the kind of lipid, rather than the amount deposited in the cells that determines cell damage. Cholesterol and saturated free fatty acids are deleterious lipids when accumulated but, in contrast, there are some valuable lipids that could counteract those with harmful properties. Much of this knowledge arises from studies using a single fatty acid, but the effects of a combination of fatty acids, as obtained by diet has been poorly addressed. In the present work, we were focused to figure out the cellular effect of two different mixes of fatty acids, one with high proportion of saturated fatty acids, and another one with high proportion of unsaturated fatty acids (Mediterranean-like) in a cellular model of steatosis. MATERIAL AND METHODS: Primary mouse hepatocytes from animals fed with a western diet (high fat and carbohydrates diet), were treated with both mixes of fatty acids for 24â¯h. RESULTS: Our data clearly show that only the high unsaturated fatty acid mix induced a decrease in triglycerides (47.5%) and cholesterol (59%) content in steatotic hepatocytes mediating cellular protection associated to the decrement of ROS and oxidative damage. The mixture of high saturated fatty acids exhibited no effects, preserving high levels of cholesterol and triglycerides and oxidative damage. In conclusion, our results show that Mediterranean-like mix of fatty acids exerts cellular protection in steatosis by decreasing triglycerides, cholesterol, ROS content and oxidative damage.
Assuntos
Dieta Mediterrânea , Dieta Ocidental , Ácidos Graxos Insaturados/farmacologia , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Antígenos de Neoplasias/efeitos dos fármacos , Células Cultivadas , Colesterol/metabolismo , Modelos Animais de Doenças , Hepatócitos/metabolismo , Hepatócitos/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos BALB C , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosfolipases A1/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Triglicerídeos/metabolismoRESUMO
Fibroblasts and macrophages play key roles in the development of hepatocellular carcinoma (HCC). However, cross-talk between these two kinds of cells has not been well studied. Endosialin (CD248/TEM1) is a transmembrane glycoprotein that is expressed in certain cancer cells, tumor stromal cells, and pericytes. In this study, we found that endosialin is mainly expressed in cancer-associated fibroblasts (CAF) in HCC and its expression inversely correlates with patient prognosis. Endosialin interacted with CD68 to recruit macrophages and regulated expression of GAS6 in CAFs to mediate M2 polarization of macrophages. The fully human antibody IgG78 bound glycosylated endosialin and induced its internalization in CAFs, thus weakening the cross-talk between CAFs and macrophages. In subcutaneous and orthotopic xenograft models of HCC in nude mice, treatment with IgG78 significantly inhibited tumor growth. These results indicate that endosialin-positive CAFs promote HCC progression and highlight IgG78 as a promising therapeutic candidate for HCC treatment. SIGNIFICANCE: These findings highlight CAF-expressed endosialin as a primary regulator of macrophage recruitment and polarization and demonstrate endosialin inhibition as a potential treatment strategy for HCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3892/F1.large.jpg.
Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígenos de Neoplasias/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Hepatocelular/metabolismo , Comunicação Celular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Hepáticas/metabolismo , Macrófagos Associados a Tumor/metabolismo , Animais , Especificidade de Anticorpos , Antígenos CD/efeitos dos fármacos , Antígenos CD/imunologia , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Fibroblastos Associados a Câncer/fisiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Movimento Celular , Polaridade Celular , Progressão da Doença , Glicosilação , Humanos , Imunoglobulina G/uso terapêutico , Fatores Imunológicos/uso terapêutico , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Camundongos , Camundongos Nus , Macrófagos Associados a Tumor/fisiologiaRESUMO
The tyrosine kinase inhibitor (TKI) sorafenib continues to be the anchor drug in the treatment of advanced stage hepatocellular carcinoma (HCC). Other TKIs as well as immune checkpoint inhibitors (ICIs) have also been approved, however the response rates remain poor and heterogeneous among HCC patients, largely due to antitumor drug resistance. Studies aimed at identifying novel biomarkers and developing new strategies to improve the response to current treatment and to overcome drug resistance, are urgently needed. Germline or somatic mutations, neoantigens, and an immunotolerogenic state against constant inflammatory stimuli in the liver, are crucial for the anti-tumor response. A pharmacogenetic approach has been attempted considering germline polymorphisms in genes encoding for proteins involved in drug-targeted pathways. Single gene and comprehensive multi-gene somatic profiling approaches have been adopted in HCC to identify tumor sensitivity scores and immunogenic profiles that can be exploited for new biomarkers and innovative therapeutic approaches. However, the high genomic heterogeneity of tumors and lack of molecularly targeted agents, hamper the discovery of specific molecular markers of resistance to therapy. Adoptive cell therapy with chimeric antigen receptor redirected T (CAR-T) cells targeting specific tumor-associated antigens (TAAs) was proposed recently. The specificity of the chosen TAA, an efficient homing of CAR-T cells to the tumor site, and the ability of CAR-T cells to survive in the tumor microenvironment are central factors in the success of CAR-T therapy. The current review describes the principal systemic treatments for HCC and the molecular evidence regarding potential predictive host and somatic genetic markers, as well as the emerging strategy of liquid biopsy for disease monitoring. Novel immunotherapeutic approaches for HCC treatment, including the use of ICIs and CAR-T, as well as strategies to overcome drug resistance, are discussed.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Antígenos Quiméricos/uso terapêutico , Sorafenibe/uso terapêutico , Inibidores da Angiogênese/farmacologia , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Antineoplásicos/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Citocinas/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Estadiamento de Neoplasias , Farmacogenética , Inibidores de Proteínas Quinases/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Radioterapia Adjuvante/métodos , Receptores de Antígenos Quiméricos/imunologia , Sorafenibe/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Fator A de Crescimento do Endotélio Vascular/imunologiaRESUMO
Tardive dystonia is one of the most serious adverse events that can be caused by antipsychotic treatment, but few studies have examined the etiology of tardive dystonia, and no genetic study using a next-generation sequencing technique has been performed to date. We conducted exome sequencing in three subjects with severe tardive dystonia. We analyzed the results focusing on candidate genes of primary dystonia, for example, TOR1A, GCH1, TH, THAP1, and SGCE. There were no single-nucleotide polymorphisms of these dystonia genes that were commonly shared among our subjects. Instead, the results revealed the presence of rare mutations (minor allele frequency <0.01) on the ZNF806 and SART3 genes in all three patients. This is the first study to analyze whole-exonic regions of the genomes of patients with tardive dystonia. These results were only preliminary, but they suggest that subjects presenting with tardive dystonia induced by antipsychotic treatment can have a genetic predisposition to tardive dystonia.
Assuntos
Antipsicóticos/efeitos adversos , Discinesia Tardia/etiologia , Discinesia Tardia/genética , Adulto , Alelos , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/genética , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Exoma/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas de Ligação a RNA/efeitos dos fármacos , Proteínas de Ligação a RNA/genética , Discinesia Tardia/metabolismo , Sequenciamento do Exoma/métodosRESUMO
We describe the synthesis of a series of 2-arylbenzimidazole derivatives bearing sulfonamide functionality (4a-d, 7a-c and 10) as well as hydroxamic acid (15a-b), carboxylic acid (16a-b), carboxamide (17a-b) and boronic acid (22a-b and 26) functionalities, which act as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. The newly synthesized benzimidazole derivatives were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IX, and XII), and especially the sulfonamide-containing benzimidazoles demonstrated intriguing inhibitory activity against tumor associated CA IX and XII with KI values in the range of 5.2-29.3 nM and 9.9-41.7 nM, respectively. Notably, compound 4c was the most potent and selective CA IX (KI = 6.6 nM) and XII (KI = 9.9 nM) inhibitor with a significant selectivity ratio over cytosolic CA I and II isoforms in the range of 3.4-25.2. In addition, compounds having hydroxamic acid (15a-b) or carboxylic acid (16a-b) functionalities resulted in greater selectivity ratios for CA IX/XII over CAI/II in the range of 4.1-121.5 although with KI values in lower micromolar potency (KIs = 0.36-0.85 µM for CA IX/XII).
Assuntos
Antígenos de Neoplasias/efeitos dos fármacos , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Anidrase Carbônica IX/efeitos dos fármacos , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Humanos , Análise Espectral/métodosRESUMO
High-potency oncology compounds such as antibody- drug conjugates, T cell redirecting, and CAR-T cell therapies have provided transformational responses in patients with liquid tumors. However, they delivered only limited benefit to solid tumor patients due to the frequent onset of dose limiting toxicities in normal tissues. Such on-target, off-tumor toxicities are caused by recognition of targets present at low-levels on normal tissues. The apparent imbalance between the rapid development of high-potency therapeutic modalities and the slow progress in identification of cleaner targets is illustrated by the fact that most high-potency compounds currently developed in the clinic target cell surface antigens identified over 20â¯years ago. Therefore, identification of novel, truly tumor-specific targets is critical for the future success of high-potency oncology compounds in solid tumors. One of the most promising approaches to overcome the limitations of targeting cell surface antigens are intracellular targets. The renewed interest in this class of targets is due to the success of immune checkpoint inhibitors, which mediate their anti-tumor responses by activation of cytotoxic T cells recognizing peptide fragments of intracellular targets presented by human leukocyte antigens (HLAs) on the surface of tumor cells. Importantly, many intracellular targets belong to the class of tumor specific antigens (TSAs), which lack presentation on normal tissues. In this report we review the main classes of tumor specific antigens, including viral, neoantigens and shared self-antigens as well as tumor associated antigens (TAAs) and their relevance for therapeutic targeting of solid tumors by high-potency therapeutic modalities.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Líquido Intracelular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/metabolismo , Antineoplásicos/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Humanos , Líquido Intracelular/metabolismo , Neoplasias/metabolismo , Resultado do TratamentoRESUMO
PURPOSE: Despite the accumulation of extensive genomic alterations, many cancers fail to be recognized as "foreign" and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options.Experimental Design: We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition in vitro and in syngeneic mouse models using genetic and pharmacologic tools. Profiling of treatment-associated tumor cell antigens was performed using immunoprecipitation followed by peptide mass spectrometry. RESULTS: We show that sustained, low-level inhibition of HSP90 both amplifies and diversifies the antigenic repertoire presented by tumor cells on MHC-I molecules through an IFNγ-independent mechanism. In stark contrast, we find that acute, high-dose exposure to HSP90 inhibitors, the only approach studied in the clinic to date, is broadly immunosuppressive in cell culture and in patients with cancer. In mice, chronic non-heat shock-inducing HSP90 inhibition slowed progression of colon cancer implants, but only in syngeneic animals with intact immune function. Addition of a single dose of nonspecific immune adjuvant to the regimen dramatically increased efficacy, curing a subset of mice receiving combination therapy. CONCLUSIONS: These highly translatable observations support reconsideration of the most effective strategy for targeting HSP90 to treat cancers and suggest a practical approach to repurposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy.See related commentary by Srivastava and Callahan, p. 6277.
Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteostase/efeitos dos fármacos , Animais , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/genética , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/imunologia , Xenoenxertos , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunoterapia/métodos , CamundongosRESUMO
A clinical oncolytic herpes simplex virus (HSV) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), talimogene laherparepvec, causes regression of injected and non-injected melanoma lesions in patients and is now licensed for clinical use in advanced melanoma. To date, limited data are available regarding the mechanisms of human anti-tumor immune priming, an improved understanding of which could inform the development of future combination strategies with improved efficacy. This study addressed direct oncolysis and innate and adaptive human immune-mediated effects of a closely related HSV encoding GM-CSF (HSVGM-CSF) alone and in combination with histone deacetylase inhibition. We found that HSVGM-CSF supported activation of anti-melanoma immunity via monocyte-mediated type I interferon production, which activates NK cells, and viral maturation of immature dendritic cells (iDCs) into potent antigen-presenting cells for cytotoxic T lymphocyte (CTL) priming. Addition of the histone deacetylase inhibitor valproic acid (VPA) to HSVGM-CSF treatment of tumor cells increased viral replication, viral GM-CSF production, and oncolysis and augmented the development of anti-tumor immunity. Mechanistically, VPA increased expression of activating ligands for NK cell recognition and induced expression of tumor-associated antigens, supporting innate NK cell killing and CTL priming. These data support the clinical combination of talimogene laherparepvec with histone deacetylase inhibition to enhance oncolysis and anti-tumor immunity.
Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Melanoma/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/metabolismo , Simplexvirus/imunologia , Neoplasias Cutâneas/terapia , Ácido Valproico/uso terapêutico , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Sobrevivência Celular/genética , Células Dendríticas/imunologia , Quimioterapia Combinada , Vetores Genéticos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Herpesvirus Humano 1 , Humanos , Interferon Tipo I/metabolismo , Células Matadoras Naturais/imunologia , Células MCF-7 , Melanoma/patologia , Vírus Oncolíticos/genética , Simplexvirus/genética , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/imunologiaRESUMO
PURPOSE: The cell surface glycoprotein Mesothelin is overexpressed in several tumor entities and novel immune-based therapies are currently under the early clinical evaluation for the treatment of malignant pleura mesothelioma, ovarian cancer, and pancreatic cancer. Cervical cancer has not been recognized as a suitable target for Mesothelin-directed immune therapies so far. METHODS: To exploit a possible role of Mesothelin in cervical cancer treatment, we analysed Mesothelin expression in 79 cervical carcinomas and aligned expressions patterns with tumor growth parameters. A novel anti-Mesothelin drug conjugate (Anetumab Ravtansine) was applied for dose-efficiency studies in a Mesothelin positive tumor model for cervical cancer in Scid mice. RESULTS: In more than three-quarters (77%) of cervical adenocarcinomas, Mesothelin was expressed to high levels. Among squamous cell carcinomas of the cervix uteri expression levels were lower and expression patterns were less intense, but still ranged between 50-60% (57%). A significant correlation between Mesothelin expression levels and tumor grade, metastatic behaviour, and lymph- or hemangiosis was not found. The novel anti-Mesothelin-drug conjugate (Anetumab Ravtansine) showed a substantial dose-dependent therapeutic efficiency in a xenotransplant model for cervical cancer in SCID mice (hela cell tumors). Applying the ADC at a dose of 10 mg/kg twice weekly induced complete tumor regression in 88% of animals within 6 weeks. CONCLUSIONS: Mesothelin should be taken into account as a target in cervical cancer therapy and histological determination of Mesothelin expression should be considered in routine diagnostics of cervical carcinomas.
Assuntos
Antígenos de Neoplasias/efeitos dos fármacos , Proteínas Ligadas por GPI/uso terapêutico , Imunoconjugados/administração & dosagem , Imunoterapia/métodos , Maitansina/análogos & derivados , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/imunologia , Animais , Feminino , Células HeLa , Humanos , Imunoconjugados/uso terapêutico , Maitansina/uso terapêutico , Mesotelina , Camundongos , Camundongos SCID , Terapia de Alvo Molecular , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: Fibrosis may be considered the hallmark of systemic sclerosis (SSc), the end stage triggered by different pathological events. Transforming growth factor-ß (TGF-ß) and platelet-derived growth factor BB (PDGF-BB) are profibrotic molecules modulating myofibroblast differentiation and proliferation, respectively. There is evidence linking CD248 with these two molecules, both highly expressed in patients with SSc, and suggesting that CD248 may be a therapeutic target for several diseases. The aim of this work was to evaluate the expression of CD248 in SSc skin and its ability to modulate SSc fibrotic process. METHODS: After ethical approval was obtained, skin biopsies were collected from 20 patients with SSc and 10 healthy control subjects (HC). CD248 expression was investigated in the skin, as well as in bone marrow mesenchymal stem cells (MSCs) treated with TGF-ß or PDGF-BB, by immunofluorescence, qRT-PCR, and Western blotting. Finally, in SSc-MSCs, the CD248 gene was silenced by siRNA. RESULTS: Increased expression of CD248 was found in endothelial cells and perivascular stromal cells of SSc skin. In SSc-MSCs, the levels of CD248 and α-smooth muscle actin expression were significantly higher than in HC-MSCs. In both SSc- and HC-MSCs, PDGF-BB induced increased expression of Ki-67 when compared with untreated cells but was unable to modulate CD248 levels. After CD248 silencing, both TGF-ß and PDGF-BB signaling were inhibited in SSc-MSCs. CONCLUSIONS: CD248 overexpression may play an important role in the fibrotic process by modulating the molecular target, leading to perivascular cells differentiation toward myofibroblasts and interfering with its expression, and thus might open a new therapeutic strategy to inhibit myofibroblast generation during SSc.
Assuntos
Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células-Tronco Mesenquimais/metabolismo , Miofibroblastos/metabolismo , Escleroderma Sistêmico/metabolismo , Adulto , Antígenos CD/efeitos dos fármacos , Antígenos de Neoplasias/efeitos dos fármacos , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/patologia , Pessoa de Meia-Idade , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Adulto JovemRESUMO
BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 µg MAGE-A3 antigen plus 420 µg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.