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1.
J Immunol Res ; 2022: 8052212, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35340585

RESUMO

With the huge therapeutic potential, cancer immunotherapy is expected to become the mainstream of cancer treatment. In the current field of cancer immunotherapy, there are mainly five types. Immune checkpoint blockade therapy is one of the most promising directions. Adoptive cell therapy is an important component of cancer immunotherapy. The therapy with the cancer vaccine is promising cancer immunotherapy capable of cancer prevention. Cytokine therapy is one of the pillars of cancer immunotherapy. Oncolytic immunotherapy is a promising novel component of cancer immunotherapy, which with significantly lower incidence of serious adverse reactions. The recent positive results of many clinical trials with cancer immunotherapy may herald good clinical prospects. But there are still many challenges in the broad implementation of immunotherapy. Such as the immunotherapy cannot act on all tumors, and it has serious adverse effects including but not limited to nonspecific and autoimmunity inflammation. Here, we center on recent progress made within the last 5 years in cancer immunotherapy. And we discuss the theoretical background, as well as the opportunities and challenges of cancer immunotherapy.


Assuntos
Vacinas Anticâncer , Neoplasias , Vacinas Anticâncer/uso terapêutico , Humanos , Fatores Imunológicos , Imunoterapia/métodos , Imunoterapia Adotiva
2.
Theranostics ; 12(12): 5488-5503, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910792

RESUMO

Rationale: Cancer immunotherapy has demonstrated significant antitumor activity in a variety of tumors; however, extensive infiltration of immunosuppressive tumor-associated macrophages (TAMs) in the glioblastoma (GBM) tumor microenvironment (TME) and the existence of the blood-brain barrier (BBB) might lead to failure of the checkpoint blockade therapy. Methods: Herein, we have developed a smart "Trojan horse" BBB-permeable nanocapsule termed "NAcp@CD47" to deliver anti-CD47 antibodies and stimulator of interferon genes (STING) agonists into GBM tissues in a stealth-like manner to reshaped the immune microenvironment by switching the phenotype of microglia and macrophages. Results: Both in vitro and in vivo studies demonstrate that NAcp@CD47 could effectively penetrate the BBB, increase the polarization of M1-phenotype TAMs, help reduce tumor immunosuppression, and inhibit the orthotopic GBM growth by phagocytosis of macrophages and microglia. Conclusions: Our findings indicate that the well-designed NAcp@CD47 not only enhances the phagocytosis of cancer cells but also efficiently enhance antitumor immunogenicity and reverses immune suppression to convert uninflamed "cold" tumors into "hot" tumors.


Assuntos
Glioblastoma , Glioma , Nanocápsulas , Glioblastoma/tratamento farmacológico , Glioma/tratamento farmacológico , Humanos , Fatores Imunológicos , Imunoterapia , Fagocitose , Microambiente Tumoral
3.
Theranostics ; 12(12): 5272-5298, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910806

RESUMO

Clinically, the conventional treatments of cancer are still often accompanied by tumor recurrence, metastasis and other poor prognosis. Nowadays, more attention has been paid to photodynamic therapy (PDT), which is regarded as an adjuvant antineoplastic strategy with superiorities in great spatiotemporal selectivity and minimal invasiveness. In addition to eliminating tumor cells via reactive oxygen species (ROS), more meaningfully, this phototherapy can trigger immunogenic cell death (ICD) that plays a vital role in photodynamic immunotherapy (PDIT). ICD-based PDIT holds some immunotherapeutic potential due to further enhanced antitumor efficacy by utilizing various combined therapies to increase ICD levels. To help the PDIT-related drugs improve pharmacokinetic properties, bioavailability and system toxicity, multifunctional nanocarriers can be reasonably designed for enhanced PDIT. In further consideration of severe hypoxia, low immunity and immune checkpoints in tumor microenvironment (TME), advanced nanotherapeutics-mediated PDIT has been extensively studied for boosting antitumor immunity by oxygen-augment, ICD-boosting, adjuvant stimulation and combined checkpoints blockade. Herein, this review will summarize different categories of nanocarriers consisting of their material type, targeting and stimuli-responsiveness. Moreover, we will focus on the latest progress of various strategies to enhance the antitumor immune effect for PDIT and elucidate their corresponding immune-activation mechanisms. Nevertheless, there are several thorny challenges in PDIT, including limited light penetration, tumor hypoxia, immune escape and the development of novel small-molecule compounds that replace immune checkpoint inhibitors (ICIs) for easy integration into nanosystems. It is hoped that these issues raised will be helpful to the preclinical study of nanotherapeutics-based PDIT, thus accelerating the transformation of PDIT to clinical practice.


Assuntos
Neoplasias , Fotoquimioterapia , Linhagem Celular Tumoral , Humanos , Morte Celular Imunogênica , Imunoterapia , Neoplasias/tratamento farmacológico , Microambiente Tumoral
4.
Oxid Med Cell Longev ; 2022: 3142306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910836

RESUMO

Immunotherapy is at the cutting edge of modern cancer treatment. Innovative medicines have been developed with varying degrees of success that target all aspects of tumor biology: tumors, niches, and the immune system. Oncolytic viruses (OVs) are a novel and potentially immunotherapeutic approach for cancer treatment. OVs reproduce exclusively in cancer cells, causing the tumor mass to lyse. OVs can also activate the immune system in addition to their primary activity. Tumors create an immunosuppressive environment by suppressing the immune system's ability to respond to tumor cells. By injecting OVs into the tumor, the immune system is stimulated, allowing it to generate a robust and long-lasting response against the tumor. The essential biological properties of oncolytic viruses, as well as the underlying mechanisms that enable their usage as prospective anticancer medicines, are outlined in this review. We also discuss the increased efficacy of virotherapy when combined with other cancer medications.


Assuntos
Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Imunoterapia , Neoplasias/patologia , Estudos Prospectivos
5.
Biomater Adv ; 138: 212867, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35913249

RESUMO

Radiotherapy (RT) is frequently utilized for cancer treatment in clinical practice and has been proved to have immune stimulation potency in recent years. However, its inhibitory effect on tumor growth, especially on tumor metastasis, is still limited by many factors, including the complex tumor microenvironment (TME). Therefore, the TME - regulating SiO2@MnO2 nanoparticles (SM NPs) were prepared and applied to the combination of RT and immunotherapy. In a bilateral animal model, SM NPs not only enhanced the inhibitory effect of RT on primary tumor growth, but also strengthened the abscopal effect to inhibit the growth of distant untreated tumors. As for the distant untreated tumor, 40% of mice showed complete inhibition of tumor growth and 40% showed a suppressed tumor growth. Moreover, SM NPs showed modulation functions for TME through inducing the increase in intracellular levels of oxygen and reactive oxygen species after their reaction with hydrogen peroxide and the main antioxidative agent glutathione in TME. Lastly, SM NPs also effectively induced the increase in the amounts of cytokines secreted by macrophage - like cells, indicating modulation functions for immune responses. This work highlighted a potential strategy of simultaneously inhibiting tumor growth and metastasis through the regulation of TME and immune responses by SM NPs - enhanced radio - immunotherapy.


Assuntos
Neoplasias , Microambiente Tumoral , Animais , Imunoterapia , Compostos de Manganês/farmacologia , Camundongos , Neoplasias/radioterapia , Óxidos/farmacologia , Dióxido de Silício/farmacologia
6.
Front Immunol ; 13: 871661, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911706

RESUMO

Different from surgery, chemical therapy, radio-therapy and target therapy, Chimeric antigen receptor-modified T (CAR-T) cells, a novel adoptive immunotherapy strategy, have been used successfully against both hematological tumors and solid tumors. Although several problems have reduced engineered CAR-T cell therapeutic outcomes in clinical trials for the treatment of thoracic malignancies, including the lack of specific antigens, an immunosuppressive tumor microenvironment, a low level of CAR-T cell infiltration into tumor tissues, off-target toxicity, and other safety issues, CAR-T cell treatment is still full of bright future. In this review, we outline the basic structure and characteristics of CAR-T cells among different period, summarize the common tumor-associated antigens in clinical trials of CAR-T cell therapy for thoracic malignancies, and point out the current challenges and new strategies, aiming to provide new ideas and approaches for preclinical experiments and clinical trials of CAR-T cell therapy for thoracic malignancies.


Assuntos
Receptores de Antígenos Quiméricos , Neoplasias Torácicas , Humanos , Imunoterapia , Imunoterapia Adotiva/efeitos adversos , Linfócitos T , Neoplasias Torácicas/tratamento farmacológico , Microambiente Tumoral
7.
J Immunol Res ; 2022: 6051092, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35915658

RESUMO

Background: In developed countries, the most common gynecologic malignancy is endometrial carcinoma (EC), making the identification of EC biomarkers extremely essential. As a natural enzyme, butyrylcholinesterase (BCHE) is found in hepatocytes and plasma. There is a strong correlation between BCHE gene mutations and cancers and other diseases. The aim of this study was to analyze the role of BCHE in patients with EC. Methods: A variety of analyses were conducted on The Cancer Genome Atlas (TCGA) data, including differential expression analysis, enrichment analysis, immunity, clinicopathology, and survival analysis. The Gene Expression Omnibus (GEO) database was used to validate outcomes. Using R tools, Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) analyses revealed the potential mechanisms of BCHE in EC. Sangerbox tools were used to delve into the relations between BCHE expression and tumor microenvironment, including microsatellite instability (MSI), tumor neoantigen count (TNC), and tumor mutation burden (TMB). BCHE's genetic alteration analysis was conducted by cBioPortal. In addition, the Human Protein Atlas (HPA) was used to validate the outcomes by immunohistochemistry, and an analysis of the protein-protein interaction network (PPI) was performed with the help of the STRING database. Results: Based on our results, BCHE was a significant independent prognostic factor for patients with EC. The prognosis with EC was affected by age, stage, grade, histological type, and BCHE. GSEA showed that BCHE was closely related to pathways regulating immune response, including transforming growth factor-ß (TGF-ß) signaling pathways and cancer immunotherapy through PD1 blockade pathways. The immune analysis revealed that CD4+ regulatory T cells (Tregs) were negatively correlated with BCHE expression and the immune checkpoint molecules CD28, ADORA2A, BTNL2, and TNFRSF18 were all significantly related to BCHE. BCHE expression was also associated with TMB by genetic alteration analysis. Conclusions: Identifying BCHE as a biomarker for EC might help predict its prognosis and could have important implications for immunotherapy.


Assuntos
Butirilcolinesterase/metabolismo , Neoplasias do Endométrio , Biomarcadores Tumorais/genética , Butirofilinas , Butirilcolinesterase/genética , Neoplasias do Endométrio/genética , Feminino , Humanos , Imunoterapia/métodos , Prognóstico , Microambiente Tumoral/genética
8.
J Immunother Cancer ; 10(8)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35922089

RESUMO

The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic.


Assuntos
Imunoterapia , Neoplasias , Anticorpos Monoclonais/uso terapêutico , Humanos , Imunoterapia/métodos , Imagem Molecular , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Tomografia por Emissão de Pósitrons/métodos
9.
Nat Commun ; 13(1): 4468, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918309

RESUMO

Bacteria-based tumor therapy has recently attracted wide attentions due to its unique capability in targeting tumors and preferentially colonizing the core area of the tumor. Various therapeutic genes are also harbored into these engineering bacteria to enhance their anti-tumor efficacy. However, it is difficult to spatiotemporally control the expression of these inserted genes in the tumor site. Here, we engineer an ultrasound-responsive bacterium (URB) which can induce the expression of exogenous genes in an ultrasound-controllable manner. Owing to the advantage of ultrasound in tissue penetration, an acoustic remote control of bacterial gene expression can be realized by designing a temperature-actuated genetic switch. Cytokine interferon-γ (IFN-γ), an important immune regulatory molecule that plays a significant role in tumor immunotherapy, is used to test the system. Our results show that brief hyperthermia induced by focused ultrasound promotes the expression of IFN-γ gene, improving anti-tumor efficacy of URB in vitro and in vivo. Our study provides an alternative strategy for bacteria-mediated tumor immunotherapy.


Assuntos
Interferon gama , Neoplasias , Bactérias/metabolismo , Citocinas , Humanos , Imunoterapia/métodos , Interferon gama/genética , Interferon gama/metabolismo , Neoplasias/genética , Neoplasias/terapia
10.
Front Immunol ; 13: 961796, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911673

RESUMO

Immunotherapy is one of the promising strategies in the treatment of oncology. Immune checkpoint inhibitors, as a type of immunotherapy, have no significant efficacy in the clinical treatment of patients with pMMR/MSS/MSI-L mCRC alone. Therefore, there is an urgent need to find combination therapies that can improve the response rate of immune checkpoint inhibitors. Oncolytic viruses are a new class of cancer drugs that, in addition to directly lysing tumor cells, can facilitate the action of immune checkpoint inhibitors by modulating the tumor microenvironment and transforming "cold" tumors into "hot" ones. The combination of oncolytic viruses and immune checkpoint inhibitors is currently being used in several primary and clinical studies to treat tumors with exciting results. The combination of genetically modified "armed" OV with ICIs is expected to be one of the treatment options for pMMR/MSS/MSI-L mCRC. In this paper, we will analyze the current status of oncolytic viruses and ICIs available for the treatment of CRC. The feasibility of OV in combination with ICI for CRC will be discussed in terms of the mechanism of action of OV in treating tumors.


Assuntos
Neoplasias Colorretais , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Instabilidade de Microssatélites , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Microambiente Tumoral
11.
Front Immunol ; 13: 927265, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911672

RESUMO

Cancer remains the second leading cause of death in the US, accounting for 25% of all deaths nationwide. Immunotherapy techniques bolster the immune cells' ability to target malignant cancer cells and have brought immense improvements in the field of cancer treatments. One important inhibitory protein in T cells, programmed cell death protein 1 (PD-1), has become an invaluable target for cancer immunotherapy. While anti-PD-1 antibody therapy is extremely successful in some patients, in others it fails or even causes further complications, including cancer hyper-progression and immune-related adverse events. Along with countless translational studies of the PD-1 signaling pathway, there are currently close to 5,000 clinical trials for antibodies against PD-1 and its ligand, PD-L1, around 80% of which investigate combinations with other therapies. Nevertheless, more work is needed to better understand the PD-1 signaling pathway and to facilitate new and improved evidence-based combination strategies. In this work, we consolidate recent discoveries of PD-1 signaling mediators and their therapeutic potential in combination with anti-PD-1/PD-L1 agents. We focus on the phosphatases SHP2 and PTPN2; the kinases ITK, VRK2, GSK-3, and CDK4/6; and the signaling adaptor protein PAG. We discuss their biology both in cancer cells and T cells, with a focus on their role in relation to PD-1 to determine their potential in therapeutic combinations. The literature discussed here was obtained from a search of the published literature and ClinicalTrials.gov with the following key terms: checkpoint inhibition, cancer immunotherapy, PD-1, PD-L1, SHP2, PTPN2, ITK, VRK2, CDK4/6, GSK-3, and PAG. Together, we find that all of these proteins are logical and promising targets for combination therapy, and that with a deeper mechanistic understanding they have potential to improve the response rate and decrease adverse events when thoughtfully used in combination with checkpoint inhibitors.


Assuntos
Antígeno B7-H1 , Neoplasias , Quinase 3 da Glicogênio Sintase , Humanos , Imunoterapia/métodos , Neoplasias/terapia , Proteína Tirosina Fosfatase não Receptora Tipo 2 , Transdução de Sinais
12.
Front Immunol ; 13: 935846, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911695

RESUMO

Commensal bacteria and other microorganisms that reside in the human body are closely associated with the development and treatment of cancers. Recently, tumor microbiome (TM) has been identified in a variety of cancers such as pancreatic, lung, and breast cancers. TM has different compositions in different tumors and has different effects on tumors. TM plays an important role in the formation of the tumor microenvironment, regulation of local immunity, and modification of tumor cell biology, and directly affects the efficacy of drug treatment for tumors. TM is expected to be a biomarker for tumors, and engineered tumor-targeting bacteria and anti-cancer microbial agents (GEN-001) have an important role in the treatment of tumors. This paper reviews the relevant studies on TM in recent years and describes its distribution in different tumors, its correlation with clinical features, its effect on local immunity, and the research directions of TM in tumor treatment.


Assuntos
Antineoplásicos , Neoplasias da Mama , Microbiota , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Bactérias , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Imunoterapia , Microambiente Tumoral
13.
Front Immunol ; 13: 952413, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911718

RESUMO

Background: Epigenetic modification regulates various aspects of cancer biology, from tumor growth and invasion to immune microenvironment modulation. Whether epigenetic regulators (EGRs) can decide tumor malignant degree and risk of immune evasion in liver hepatocellular carcinoma (LIHC) remains unclear. Method: An EGR signature called "EGRscore" was constructed based on bulk RNA-seq data of EGR in hepatocellular carcinoma (HCC). The correlation between EGRscore and overall survival (OS) was validated in HCC cohorts and other tumor cohorts. Mutation profiles, copy number alterations (CNAs), enriched pathways, and response to immunotherapy and chemotherapy were compared between EGRscore-high and EGRscore-low patients. Results: We found that EGRscore was associated with OS in HCC as well as several tumors including glioma, uveal melanoma (UVM), and kidney tumors. A mechanism study demonstrated that the distinct mutation profile of TP53 was present in EGRscore-high and EGRscore-low patients. Meanwhile, EGRscore-low patients were characterized with immune cells that promote killing tumors. Furthermore, EGRscore was associated with genes regulating drug resistance in HCC. Finally, we indicated that EGRscore-low patients had higher response rates to immunotherapy and targeted therapy. Conclusions: EGRscore could be used to distinguish OS, tumor progression, mutation pattern, and immune microenvironment. The present study contributes to improving hepatocellular carcinoma patient prognosis and predicting response to immunotherapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Epigênese Genética , Humanos , Imunoterapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Prognóstico , Microambiente Tumoral/genética
14.
Front Immunol ; 13: 940674, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35911742

RESUMO

The clinical use of anti-CD40 agonist monoclonal antibodies (mAbs) is aimed at recruiting the immune system to fight the tumor cells. This approach has been demonstrated to be effective in various preclinical models. However, human CD40 Abs displayed only modest antitumor activity in cancer patients, characterized by low efficacy and dose-limiting toxicity. While recent studies highlight the importance of engineering the Fc region of human CD40 mAbs to optimize their agonistic potency, toxicity remains the main limiting factor, restricting clinical application to suboptimal doses. Here, we discuss the current challenges in realizing the full potential of CD40 mAbs in clinical practice, and describe novel approaches designed to circumvent the systemic toxicity associated with CD40 agonism.


Assuntos
Antineoplásicos Imunológicos , Antineoplásicos , Neoplasias , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígenos CD40 , Linhagem Celular Tumoral , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico
15.
Eur Rev Med Pharmacol Sci ; 26(14): 5014-5032, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35916798

RESUMO

OBJECTIVE: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death, with high morbidity and low survival. Research on the relationship between cancer cells and oxidative stress has rapidly increased in recent years. Therefore, finding new therapeutic and prognostic targets for hepatocellular carcinoma based on oxidative stress-related genes (OSRGs) has far-reaching significance. MATERIALS AND METHODS: We first obtained OSRGs on GeneCards and then, based on the TCGA database, compared tumor tissues with normal tissues. Using the LASSO Cox regression method, we obtained six differentially expressed genes associated with prognosis. We also divided all HCC patients in the TCGA cohort into a low-risk group and a high-risk group based on these six genes and accordingly performed a correlation analysis of differentially expressed oxidative-stress-related genes (DEOSRGs). These analyses included GSEA, PPI, survival analysis, immune correlation analysis, tumor microenvironment correlation analysis, m6A analysis, gene mutation analysis, drug-sensitivity analysis, and molecular docking validation. The reliability of the model genes was further verified using a multi-platform database, qRT-PCR and MTT assay. RESULTS: These six genes may play an important role in the prognosis of hepatocellular carcinoma patients by affecting the kinase, carboxylic acid synthesis and metabolism, ROS production, lipid oxidation and immune response. Validation experiment results further confirm that these model genes are good indicators for the diagnosis and prognosis of hepatocellular carcinoma. CONCLUSIONS: This study analyzed the prognosis and function of HCC prognosis-related differential genes, predicted that the prognosis-related differential genes played an essential role in HCC immunity, and proposed therapeutic targets and biomarkers for HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica/métodos , Humanos , Imunoterapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Simulação de Acoplamento Molecular , Estresse Oxidativo , Prognóstico , Reprodutibilidade dos Testes , Microambiente Tumoral/genética
16.
MAbs ; 14(1): 2088454, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35924382

RESUMO

Monoclonal antibodies targeting the programmed cell death protein 1 (PD-1) remain the most prevalent cancer immunotherapy both as a monotherapy and in combination with additional therapies. Despite the extensive success of anti-PD-1 monoclonal antibodies in the clinic, the experimental relationship between binding affinity and functional potency for anti-PD-1 antibodies in vivo has not been reported. Anti-PD-1 antibodies with higher and lower affinity than nivolumab or pembrolizumab are entering the clinic and show varied preclinical efficacy. Here, we explore the role of broad-ranging affinity variation within a single lineage in a syngeneic immunocompetent mouse model. By developing a panel of murine anti-PD-1 antibodies with varying affinity (ranging from KD = 20 pM - 15 nM), we find that there is a threshold affinity required for maximum efficacy at a given dose in the treatment of the MC38 adenocarcinoma model with anti-PD-1 immunotherapy. Physiologically based pharmacokinetic modeling complements interpretation of the experimental results and highlights the direct relationship between dose, affinity, and PD-1 target saturation in the tumor.


Assuntos
Anticorpos Monoclonais , Imunoterapia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Fatores Imunológicos , Imunoterapia/métodos , Camundongos , Nivolumabe
17.
Inn Med (Heidelb) ; 63(8): 851-862, 2022 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-35925070

RESUMO

Pancreatic cancer is the 4th most common cause of cancer death in Germany and continues to be associated with a poor prognosis. A prerequisite for chemotherapy or radiotherapy is always the pathohistological (or cytological) confirmation of the tumor disease. Molecular diagnostics include analysis of DNA mismatch repair in the tumor and of the germline mutations in BRCA 1/2 (gBRCA mutation). Systemic chemotherapy remains the mainstay in the management of locally advanced and metastatic disease. If a gBRCA mutation is detected, platinum-based therapy should be used. Patients with good performance status benefit from second-line therapy. Immunotherapy with checkpoint inhibitors (not yet approved) may be considered in pretreated patients with evidence of deficient DNA mismatch repair or microsatellite instability.


Assuntos
Neoplasias Pancreáticas , Reparo de Erro de Pareamento de DNA/genética , Mutação em Linhagem Germinativa , Humanos , Imunoterapia , Instabilidade de Microssatélites , Neoplasias Pancreáticas/tratamento farmacológico
18.
Urologie ; 61(6): 587-595, 2022 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-35925079

RESUMO

BACKGROUND: A multitude of treatment options for the systemic treatment of urologic cancer have become available in recent years. In addition to classical chemotherapy or androgen-deprivation therapy, other approaches like targeted therapies (e.g., tyrosine kinase inhibitors), checkpoint inhibitors, and new approaches like radioligand therapies are increasingly used. Whether treating their own patients or caring for patients who receive these compounds from other physicians in the field, urologists will inevitably be confronted with adverse events associated with these diverse therapies. This development will continue to grow as new compounds are continuously being registered and even new drug classes are being developed. Therefore, every urologist should know the basics regarding prophylaxis, control of adverse events, and especially management of emergency situations associated with systemic treatment in uro-oncology. OBJECTIVES: To provide an overview of typical emergency situations and their management in genitourinary cancers. METHODS: Summary of common uro-oncological emergency situations associated with systemic therapy. RESULTS: The urologist requires expert knowledge in the management of emergencies within systemic treatment of genitourinary cancers like neutropenic fever during chemotherapy, hand-foot syndrome with tyrosine kinase inhibitors, immune-related adverse events, but also of side effects occurring in patients treated by other physicians, e.g., during radioligand therapies administered by nuclear physicians. CONCLUSIONS: Basic knowledge on the typical side effects and emergencies that are associated with compounds used in the treatment of genitourinary cancers is essential. Continuous medical education to be able to handle the new developments in this rapidly evolving field is mandatory.


Assuntos
Antagonistas de Androgênios , Neoplasias da Próstata , Emergências , Humanos , Imunoterapia/efeitos adversos , Masculino , Neoplasias da Próstata/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos
19.
Inn Med (Heidelb) ; 63(7): 709-716, 2022 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-35925267

RESUMO

Within a few years the introduction of immune checkpoint inhibitors (ICI) fundamentally changed the treatment landscape of patients with metastatic non-small cell lung cancer (NSCLC) and improved survival for a relevant proportion of patients. Immune monotherapies are highly efficient in cancers showing a PD-L1 overexpression ≥ 50% of tumor cells, all others with a lower level and independent from the PD-L1 expression can be treated with various treatment combinations. In a curative setting all PD-L1 positive patients (≥ 1%) who underwent chemoradiotherapy to reduce disease relapse and subsequently to improve survival should undergo an ICI maintenance treatment. Furthermore, positive results from phase III studies are also available for adjuvant treatment of patients with resectable NSCLC, whereby an EMA approval is currently pending. The treatment with ICIs has given rise to a new class of immune-mediated adverse side effects, which occur in approximately one third of the patients and range from easily substituted endocrinopathies to life-threatening organ toxicity. An anticipatory monitoring as well as interdisciplinary treatment are therefore the keys to avoiding progression of higher grade potentially fatal toxicities.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Fatores Imunológicos/uso terapêutico , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico
20.
Inn Med (Heidelb) ; 63(7): 717-723, 2022 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-35925268

RESUMO

Treatment concepts for patients with localized and locally advanced non-small cell lung cancer (NSCLC) are based on local treatment, surgery and/or radiotherapy, with curative intent. An adjuvant systemic treatment is added after primary resection of an operable NSCLC primarily to reduce the systemic risk of relapse. Locally advanced stages with mediastinal lymph node involvement carry a substantial risk of local and distant recurrence and require multimodal treatment strategies in an interdisciplinary approach. Recently, immunotherapy with programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) checkpoint inhibitors is increasingly being integrated into adjuvant, neoadjuvant or perioperative treatment concepts.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Imunoterapia , Neoplasias Pulmonares/terapia , Terapia Neoadjuvante , Recidiva Local de Neoplasia
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