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1.
Psychooncology ; 31(1): 107-115, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34425036

RESUMO

OBJECTIVE: CanCope is an internet-delivered, cognitive-behavioural intervention adapted from the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders to improve emotion regulation and support the mental health of cancer survivors. Four separate pilot studies evaluated each of CanCope's modules for (1) feasibility and participant satisfaction, and changes in (2) module-specific outcomes, and (3) global measures of emotion dysregulation and anxiety and depressive symptoms, from pre-to-post module delivery. METHODS: Eligible cancer survivors self-selected into one two-week online module designed to improve a specific aspect of emotion regulation ([1] understanding emotions, [2] mindfulness of emotions, [3] cognitive reappraisals, [4] challenging emotion-driven behaviours). RESULTS: Across modules, post-intervention surveys were completed by 17-19 participants, (58.1%-90.5% completion rate for participants who received the intervention). Each module was feasible and participants reported high satisfaction. Moderate-to-large pre-to-post effect sizes in mean differences were observed in module-specific target outcomes (p's < 0.05). Emotion dysregulation significantly decreased across modules 1 to 3 (p's < 0.05) with a non-significant decrease for module 4 (p = 0.13). Anxiety symptoms significantly decreased across all modules (p's < 0.05). Depressive symptoms significantly decreased across modules 1 and 3 (p's < 0.05), with non-significant decreases across modules 2 (p = 0.08) and 4 (p = 0.06). CONCLUSIONS: Each CanCope module demonstrated promise in targeting emotion regulation skills and supporting the mental health of cancer survivors. Randomised controlled trials are required to test the efficacy of CanCope as an intervention in its entirety.


Assuntos
Sobreviventes de Câncer , Terapia Cognitivo-Comportamental , Intervenção Baseada em Internet , Neoplasias , Transtornos de Ansiedade/terapia , Sobreviventes de Câncer/psicologia , Terapia Cognitivo-Comportamental/métodos , Humanos , Saúde Mental , Neoplasias/terapia
2.
In Vivo ; 36(2): 898-906, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35241548

RESUMO

BACKGROUND/AIM: An early evaluation concerning the effectiveness of supportive oligonucleotide therapy (SOT) in cancer as a monotherapy and in combination with other types of treatment. PATIENTS AND METHODS: This study evaluated the clinical condition and performance status (Karnofsky-Index) of 95 patients, post-SOT administration. Furthermore, circulating tumor cells (CTCs) from 47 patients' pre- and post-SOT administration were measured and analyzed by repeated-measures ANOVA. RESULTS: Improvement of the clinical condition was observed in all patients who used SOT (77.89%), SOT in combination with other therapy (69.77%) and SOT as a monotherapy or no information was given concerning another therapy (84.31%). Positive results for Karnofsky-Index were also observed in 71.58%, 61.36%, and 80.39%, respectively. Finally, statistically significant reductions in CTCs were observed for both SOT as a monotherapy and SOT as an adjunctive therapy. CONCLUSION: The preliminary results indicate that SOT therapy can be used both as monotherapy as well as in combination with other therapies for cancer.


Assuntos
Neoplasias , Oligonucleotídeos , Humanos , Neoplasias/terapia , Oligonucleotídeos/uso terapêutico
3.
Clin. transl. oncol. (Print) ; 24(9): 1682–1701, septiembre 2022. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-JHG-503

RESUMO

With the in-depth research and wide application of immunotherapy recently, new therapies based on oncolytic viruses are expected to create new prospects for cancer treatment via eliminating the suppression of the immune system by tumors. Currently, an increasing number of viruses are developed and engineered, and various virus vectors based on effectively stimulating human immune system to kill tumor cells have been approved for clinical treatment. Although the virus can retard the proliferation of tumor cells, the choice of oncolytic viruses in biological cancer therapy is equally critical given their therapeutic efficacy, safety and adverse effects. Moreover, previously known oncolytic viruses have not been systematically classified. Therefore, in this review, we summarized and distinguished the characteristics of several common types of oncolytic viruses: herpes simplex virus, adenovirus, measles virus, Newcastle disease virus, reovirus and respiratory syncytial virus. Subsequently, we outlined that these oncolytic viral vectors have been transformed from preclinical studies in combination with immunotherapy, radiotherapy, chemotherapy, and nanoparticles into clinical therapeutic strategies for various advanced solid malignancies or circulatory system cancers. (AU)


Assuntos
Humanos , Vetores Genéticos , Imunoterapia , Neoplasias/terapia , Vírus Oncolíticos/genética , Terapia Viral Oncolítica
4.
Biomater Adv ; 138: 212919, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35913232

RESUMO

Photothermal therapy (PTT) usually causes hyperthermia and damages healthy tissues. Developing a PTT platform with enhanced therapeutic effects and reduced side effects to normal tissues attracts increasing attention. Herein, we developed a multifunctional theranostic nanoplatform using poly(lactic-co-glycolic acid) (PLGA) loaded with near-infrared (NIR) photothermal agent (new indocyanine green IR820), fluorescence imaging agent (ZnCdSe/ZnS quantum dots, QDs) and autophagy inhibitor (chloroquine, CQ). These PLGA/IR820/Fluorescence imaging agent/CQ co-loading nanoparticles (termed PIFC NPs) displayed photothermal effects, enhanced the stability of IR820 in vivo, and enabled QDs to have stable fluorescent signals in vitro and in vivo. The PIFC NPs with particle size around 240 nm aggregated to tumor sites through the high permeability and retention effects of solid tumors. The intracellular delivery of CQ molecules through PIFC NPs significantly attenuated the degradation of autophagic lysosomes in tumor cells and effectively inhibited the autophagy mediated repair of photothermal damaged cells. Under milder NIR irradiation conditions, PIFC NPs exhibited high antitumor effect. By regulating autophagy, PTT can be effectively sensitized, which will provide a new idea for future cancer treatment research.


Assuntos
Hipertermia Induzida , Neoplasias , Autofagia , Humanos , Neoplasias/terapia , Fototerapia/métodos , Terapia Fototérmica , Medicina de Precisão
5.
Biomater Adv ; 138: 212938, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35913234

RESUMO

Photothermal nanoparticles are important in photothermal therapy. Combining different nanoparticles can achieve a high photothermal capacity. In this study, composite nanoparticles composed of black phosphorus nanosheets (BPNSs) and gold nanostars (BP-AuNSs) were synthesized by using BPNSs as the reductant. AuNSs were deposited on the BPNSs. The BP-AuNSs were further hybridized with porous gelatin scaffolds to prepare gelatin-BP-AuNS composite scaffolds. The gelatin-BP-AuNS composite scaffolds promoted cell migration and distribution. The synergistic effects of the BPNSs and AuNSs endowed the gelatin-BP-AuNS composite scaffolds with excellent photothermal properties. The gelatin-BP-AuNS composite scaffolds eliminated cancer cells after near infrared laser exposure and supported the adipogenic differentiation of human mesenchymal stem cells. Thus, this gelatin-BP-AuNS composite scaffold holds promise for breast cancer therapy.


Assuntos
Gelatina , Neoplasias , Diferenciação Celular , Ouro , Humanos , Neoplasias/terapia , Fósforo , Células-Tronco
6.
JCO Clin Cancer Inform ; 6: e2200006, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35917480

RESUMO

PURPOSE: The advancement of natural language processing (NLP) has promoted the use of detailed textual data in electronic health records (EHRs) to support cancer research and to facilitate patient care. In this review, we aim to assess EHR for cancer research and patient care by using the Minimal Common Oncology Data Elements (mCODE), which is a community-driven effort to define a minimal set of data elements for cancer research and practice. Specifically, we aim to assess the alignment of NLP-extracted data elements with mCODE and review existing NLP methodologies for extracting said data elements. METHODS: Published literature studies were searched to retrieve cancer-related NLP articles that were written in English and published between January 2010 and September 2020 from main literature databases. After the retrieval, articles with EHRs as the data source were manually identified. A charting form was developed for relevant study analysis and used to categorize data including four main topics: metadata, EHR data and targeted cancer types, NLP methodology, and oncology data elements and standards. RESULTS: A total of 123 publications were selected finally and included in our analysis. We found that cancer research and patient care require some data elements beyond mCODE as expected. Transparency and reproductivity are not sufficient in NLP methods, and inconsistency in NLP evaluation exists. CONCLUSION: We conducted a comprehensive review of cancer NLP for research and patient care using EHRs data. Issues and barriers for wide adoption of cancer NLP were identified and discussed.


Assuntos
Processamento de Linguagem Natural , Neoplasias , Registros Eletrônicos de Saúde , Humanos , Armazenamento e Recuperação da Informação , Neoplasias/diagnóstico , Neoplasias/terapia , Assistência ao Paciente
7.
JCO Glob Oncol ; 8: e2200043, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35917484

RESUMO

PURPOSE: With successive infection waves and the spread of more infectious variants, the COVID-19 pandemic continues to have major impacts on health care. To achieve best outcomes for patients with cancer during a pandemic, efforts to minimize the increased risk of severe pandemic infection must be carefully balanced against unintended adverse impacts of the pandemic on cancer care, with consideration to available health system capacity. Cancer Australia's conceptual framework for cancer care during a pandemic provides a planning resource for health services and policy-makers that can be broadly applied globally and to similar pandemics. METHODS: Evidence on the impact of the COVID-19 pandemic on cancer care and health system capacity to June 2021 was reviewed, and the conceptual framework was developed and updated. RESULTS: Components of health system capacity vary during a pandemic, and capacity relative to pandemic numbers and severity affects resources available for cancer care delivery. The challenges of successive pandemic waves and high numbers of pandemic cases necessitate consideration of changing health system capacity in decision making about cancer care. Cancer Australia's conceptual framework provides guidance on continuation of care across the cancer pathway, in the face of challenges to health systems, while minimizing infection risk for patients with cancer and unintended consequences of delays in screening, diagnosis, and cancer treatment and backlogs because of service interruption. CONCLUSION: Evidence from the COVID-19 pandemic supports continuation of cancer care wherever possible during similar pandemics. Cancer Australia's conceptual framework, underpinned by principles for optimal cancer care, informs decision making across the cancer care continuum. It incorporates consideration of changes in health system capacity and capacity for cancer care, in relation to pandemic progression, enabling broad applicability to different global settings.


Assuntos
COVID-19 , Neoplasias , Atenção à Saúde , Programas Governamentais , Humanos , Neoplasias/terapia , Pandemias/prevenção & controle , SARS-CoV-2
8.
Biomater Adv ; 136: 212794, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35929333

RESUMO

Malignant tumors, particularly those located in deep tissues, have always been a grievous threat to human health. Sonodynamic therapy (SDT) has recently attracted great attention due to deep tissue penetration. However, the lack of effective sonosensitizers and the poor therapeutic efficacy severely limit their wider use. Herein, dual-functionalized black phosphorus nanosheets (BP@PEI-PEG, i.e., PPBP) integrating black oxygen-deficient titanium dioxide particles (B-TiO2) were successfully constructed (PPBP-B-TiO2) for synergistic photothermal (PTT)/sonodynamic therapy. In these nanocomposites, black titanium dioxide can enhance the separation of electrons (e-) and holes (h+) due to the oxygen-deficient structure and significantly improves the production of reactive oxygen species (ROS) for SDT, while the BP nanosheets endow the nanocomposites with a higher photothermal conversion capability for photothermal therapy (η = 44.1%) which can prolong the blood circulation and improve the O2 supply. In vivo experiments prove that PPBP-B-TiO2 nanocomposites exhibited outstanding tumor inhibition efficacy and excellent biocompatibility. This work provides a prospective platform for combined photothermal/sonodynamic cancer therapy.


Assuntos
Neoplasias , Fósforo , Linhagem Celular Tumoral , Humanos , Neoplasias/terapia , Oxigênio/farmacologia , Fósforo/química , Titânio/farmacologia
9.
Curr Opin Support Palliat Care ; 16(3): 110-116, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35929557

RESUMO

PURPOSE OF REVIEW: Over the past 2 years, the COVID-19 pandemic has had short-term and long-term effects on the delivery of cancer care. Some European countries faced an unprecedented widespread crisis during the first year of the SARS-CoV-2 pandemic, only being able afterwards to gradually recover, thanks to the improvement in preventive measures, changes in public health and reactive processes in cancer care and a better understanding of the ongoing heath emergency. RECENT FINDINGS: The development of SARS-CoV-2 vaccines and COVID-19 specific treatments, the growing testing and tracking capability to limit virus diffusion, and research efforts to better define areas of action have all greatly limited the negative impact of the health emergency on routine cancer care.The need to protect those more vulnerable and to ensure continuity of care for oncology patients has been balanced across the pandemic, with the aim to guarantee an optimal standard of care. SUMMARY: This article aims to provide an overview on the evolving scenario of cancer care throughout the COVID-19 pandemic in Europe, focusing on the particular features that characterized the pandemic course as well as the main differences that were observed across it.


Assuntos
COVID-19 , Neoplasias , COVID-19/epidemiologia , Vacinas contra COVID-19 , Europa (Continente)/epidemiologia , Humanos , Neoplasias/epidemiologia , Neoplasias/terapia , Pandemias/prevenção & controle , SARS-CoV-2
10.
Curr Opin Support Palliat Care ; 16(3): 138-143, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35929560

RESUMO

PURPOSE OF REVIEW: To summarize the current literature on the psychological impact of COVID-19 on patients with cancer, both in terms of the impact of the virus itself and of changes in the healthcare system; and to describe current recommendations for supporting patients with cancer during the pandemic. RECENT FINDINGS: Multiple studies have shown that patients with cancer experience high levels of psychological distress during COVID-19. Factors of greater vulnerability have been described as: being young, being female, low socioeconomic status, lower educational level, having low levels of hope or optimism, lower social support, and having cancer with curative intent. The severe acute respiratory syndrome-coronavirus-2pandemic has accelerated the healthcare digitization process. All departments involved in the diagnosis and treatment of cancer have made contingency plans to minimize the impact on patients. SUMMARY: Psychological distress is one of the most frequently occurring symptoms in patients with cancer during the pandemic. The COVID-19 pandemic has led to a restructuring of the healthcare system. The paradigm shift may pose a challenge for both healthcare professionals and patients.


Assuntos
COVID-19 , Neoplasias , COVID-19/epidemiologia , Feminino , Pessoal de Saúde/psicologia , Humanos , Masculino , Neoplasias/epidemiologia , Neoplasias/terapia , Pandemias , SARS-CoV-2
11.
Curr Opin Support Palliat Care ; 16(3): 161-167, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35929562

RESUMO

PURPOSE OF REVIEW: For decades, clinical decision making and practice has been largely informed by data generated through randomized clinical trials (RCTs). By design, RCTs are highly restricted in both scope and scale, resulting in narrow indications and iterative advances in clinical practice. With the transition to electronic health records, there are now endless opportunities to utilize these 'real world' data (RWD) to make more substantive advances in our understanding that are, by nature, more applicable to reality. This review discusses the current paradigm of using big data to advance and inform the provision of supportive cancer care, using mucositis as a case study. RECENT FINDINGS: Global efforts to synthesize RWD in cancer have almost exclusively focused on tumor classification and treatment efficacy, leveraging on routine tumor pathology and binary response outcomes. In contrast, clinical notes and billing codes are not as applicable to treatment side effects which require integration of both clinical and biological data, as well as patient-reported outcomes. SUMMARY: Cancer treatment-induced toxicities are heterogeneous and complex, and as such, the use of RWD to better understand their etiology and interaction is challenging. Multidisciplinary cooperation and leadership are needed to improve data collection and governance to ensure the right data is accessible and reliable.


Assuntos
Mucosite , Neoplasias , Tomada de Decisão Clínica , Coleta de Dados/métodos , Humanos , Neoplasias/complicações , Neoplasias/terapia
12.
Front Immunol ; 13: 925985, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936003

RESUMO

Chimeric antigen receptor (CAR)-T cell therapy is a progressive new pillar in immune cell therapy for cancer. It has yielded remarkable clinical responses in patients with B-cell leukemia or lymphoma. Unfortunately, many challenges remain to be addressed to overcome its ineffectiveness in the treatment of other hematological and solidtumor malignancies. The major hurdles of CAR T-cell therapy are the associated severe life-threatening toxicities such as cytokine release syndrome and limited anti-tumor efficacy. In this review, we briefly discuss cancer immunotherapy and the genetic engineering of T cells and, In detail, the current innovations in CAR T-cell strategies to improve efficacy in treating solid tumors and hematologic malignancies. Furthermore, we also discuss the current challenges in CAR T-cell therapy and new CAR T-cell-derived nanovesicle therapy. Finally, strategies to overcome the current clinical challenges associated with CAR T-cell therapy are included as well.


Assuntos
Neoplasias Hematológicas , Neoplasias , Terapia Genética/efeitos adversos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Humanos , Imunoterapia Adotiva/efeitos adversos , Neoplasias/genética , Neoplasias/terapia , Linfócitos T
13.
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
14.
Sci Rep ; 12(1): 13329, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35922531

RESUMO

Six members of the gasdermin family are involved in various biological functions in malignant tumors. The present study aimed to perform a comprehensive analysis of gasdermin family genes in pan-cancer. Raw data was acquired from the genotype-tissue expression (GTEx) and the Cancer Genome Atlas. High inter-tumor heterogeneity in the expression between paracancerous and tumor tissues was observed across cancers. Survival analysis confirmed that the risk or protective effects of gasdermin family members on prognosis depended on the cancer types. The mutation frequency appeared to be high, and the mutation group had a worse prognosis. Besides, gasdermin family genes were associated with immune infiltrate subtypes, stromal and immune cell infiltration levels, TMB, MSI, immune checkpoint gene expression, and tumor stemness scores. Moreover, gasdermin family gene expressions affected the expressions of MMR genes and methyltransferases and could predict cancer cells sensitivity to chemotherapeutic drugs. Subsequently, the findings were double-checked in LIHC and PAAD. GSEA results indicated the gasdermin family genes mainly involved in tumor metabolism and immune microenvironment remodeling related signaling pathways. In conclusion, our findings confirmed that gasdermin family genes were potential therapeutic cancer targets in pan-cancer.


Assuntos
Biomarcadores Tumorais , Neoplasias , Biomarcadores Tumorais/genética , Família , Humanos , Neoplasias/genética , Neoplasias/terapia , Prognóstico , Análise de Sobrevida , Microambiente Tumoral/genética
16.
BMC Psychiatry ; 22(1): 533, 2022 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-35931980

RESUMO

INTRODUCTION: Cancer is a primary and challenging health problem, has a significant impact on caregivers, and is a leading cause of emotional responses like depression. Depression is the most common and serious psychiatric disorder that has a considerable effect on the daily life of primary caregivers. Different articles reported that the magnitude of depression was prevalent among primary caregivers of patients with cancer. There is scarcity of published articles about the problem in Ethiopia. This study aimed to assess the prevalence of depression and associated factors among primary caregivers of adult cancer patients at Northwest Amhara Regional States Referrals Hospitals, oncology treatment units, Northwest Ethiopia, 2021. METHODS: An institutional-based cross-sectional study was conducted in Northwest Amhara Regional States Referrals Hospitals. A systematic random sampling technique was used to select 421 participants. The data were collected using interviewer-administered and chart review through structured, pretested Patient Health Questionarie-9 questionnaires. The data were entered into Epi. Data version 4.6 and analyzed using Stata version 14.0. Bivariable and multivariable logistic regression were carried out to identify factors associated with depression. Adjusted odds ratio with a 95% confidence interval and variables with a p-value < 0.05 were considered significantly associated with depression. RESULTS: The prevalence of depression was 45.15%. Being female (AOR = 2.01, 95%, CI: 1.27-3.19), having an average monthly income of < 1000 Ethiopian birr (AOR = 3.54, 95% CI: 1.54-8.13), and primary caregivers of a cancer patient with mixed therapy (AOR = 4.54, 95%, CI: (1.5-13.48) were significantly associated with depression. CONCLUSION: The prevalence of depression among primary caregivers of adult patients with cancer was significant. It's better, health care providers in oncology treatment facilities need to recognize and screen and give special attention to female primary caregivers, having an average monthly income of < 1000 Ethiopian birr, and primary caregivers of a cancer patient with mixed therapy to reduce the risk of developing depression.


Assuntos
Cuidadores , Neoplasias , Adulto , Estudos Transversais , Depressão/epidemiologia , Etiópia/epidemiologia , Feminino , Hospitais , Humanos , Masculino , Neoplasias/epidemiologia , Neoplasias/terapia , Prevalência , Encaminhamento e Consulta
17.
Front Immunol ; 13: 951247, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935945

RESUMO

Background: Immunotherapy has achieved great success in cancer. Nevertheless, many patients cannot benefit from immune checkpoint blockade therapy because of the scantiness of CD8+ T cell infiltration in the tumor microenvironment (TME). CXCL11 is known as a regulator that influences T-cell infiltration into tumors. However, the role of CXCL11 in pan-cancer is still unclear. Methods: In this study, we investigated the expression and function of CXCL11 across 33 types of cancers based on datasets from The Cancer Genome Atlas (TCGA) database and the Genotype-Tissue Expression (GTEx) database. We analyzed the CXCL11 differential expression in tumor tissue and nontumoral tissue and in different stages of cancers. Moreover, the correlations among CXCL11 expression, prognosis, mismatch repair, tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment, and immune-related genes were evaluated. Results: CXCL11 expression was significantly higher in tumoral tissue than in nontumoral tissue for most types of cancer. Improved CXCL11 expression was related to an inconsistent prognosis in different cancers. CXCL11 was positively associated with CD8+ T cells and T follicular helper cells in the TME. High expression of CXCL11 was positively related to TMB in BLCA, BRCA, CESC, COAD, LGG, LUAD, OV, SKCM, STAD, THYM, and UCEC. A positive correlation between CXCL11 and MSI was found in COAD and UVM. Moreover, functional analysis of CXCL11 showed that high CXCL11 expression was significantly related to immune-relevant pathways. Conclusions: CXCL11 might function as a prognostic and immunotherapy marker across cancers. Further investigation into CXCL11 might provide promising insights to improve cancer therapy.


Assuntos
Quimiocina CXCL11/metabolismo , Imunoterapia , Neoplasias , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos , Quimiocina CXCL11/genética , Humanos , Fatores Imunológicos , Instabilidade de Microssatélites , Neoplasias/genética , Neoplasias/patologia , Neoplasias/terapia , Prognóstico , Microambiente Tumoral
18.
JAMA ; 328(6): 518, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35943484
19.
Proc Natl Acad Sci U S A ; 119(32): e2200879119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35925889

RESUMO

The value of anti-CTLA-4 antibodies in cancer therapy is well established. However, the broad application of currently available anti-CTLA-4 therapeutic antibodies is hampered by their narrow therapeutic index. It is therefore challenging and attractive to develop the next generation of anti-CTLA-4 therapeutics with improved safety and efficacy. To this end, we generated fully human heavy chain-only antibodies (HCAbs) against CTLA-4. The hIgG1 Fc domain of the top candidate, HCAb 4003-1, was further engineered to enhance its regulatory T (Treg) cell depletion effect and to decrease its half-life, resulting in HCAb 4003-2. We tested these HCAbs in in vitro and in vivo experiments in comparison with ipilimumab and other anti-CTLA4 antibodies. The results show that human HCAb 4003-2 binds human CTLA-4 with high affinity and potently blocks the binding of B7-1 (CD80) and B7-2 (CD86) to CTLA-4. The results also show efficient tumor penetration. HCAb 4003-2 exhibits enhanced antibody-dependent cellular cytotoxicity function, lower serum exposure, and more potent anti-tumor activity than ipilimumab in murine tumor models, which is partly driven by a substantial depletion of intratumoral Tregs. Importantly, the enhanced efficacy combined with the shorter serum half-life and less systemic drug exposure in vivo potentially provides an improved therapeutic window in cynomolgus monkeys and preliminary clinical applications. With its augmented efficacy via Treg depletion and improved safety profile, HCAb 4003-2 is a promising candidate for the development of next generation anti-CTLA-4 therapy.


Assuntos
Cadeias Pesadas de Imunoglobulinas , Imunoterapia , Neoplasias , Linfócitos T Reguladores , Animais , Citotoxicidade Celular Dependente de Anticorpos , Antígeno CTLA-4/imunologia , Humanos , Cadeias Pesadas de Imunoglobulinas/farmacologia , Ipilimumab/farmacologia , Camundongos , Neoplasias/patologia , Neoplasias/terapia
20.
Curr Opin Oncol ; 34(5): 579-586, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35943441

RESUMO

PURPOSE OF REVIEW: Here, we reviewed the recent breakthroughs in the understanding of predictive biomarkers for immune checkpoint inhibitors (ICI) treatment. RECENT FINDINGS: ICI have revolutionized cancer therapy enabling novel therapeutic indications in multiple tumor types and increasing the probability of survival in patients with metastatic disease. However, in every considered tumor types only a minority of patients exhibits clear and lasting benefice from ICI treatment, and due to their unique mechanism of action treatment with ICI is also associated with acute clinical toxicities called immune related adverse events (irAEs) that can be life threatening. The approval of the first ICI drug has prompted many exploratory strategies for a variety of biomarkers and have shown that several factors might affect the response to ICI treatment, including tumors intrinsic factors, tumor microenvironment and tumor extrinsic or systemic factor. Currently, only three biomarkers programmed death-ligand 1 (PD-L1), tumor microenvironment and microsatellite instability had the US Food and Drug Administration-approbation with some limitations. SUMMARY: The establishment of valid predictive biomarkers of ICI sensitivity has become a priority to guide patient treatment to maximize the chance of benefit and prevent unnecessary toxicity.


Assuntos
Neoplasias , Receptor de Morte Celular Programada 1 , Humanos , Imunoterapia/efeitos adversos , Instabilidade de Microssatélites , Neoplasias/terapia , Microambiente Tumoral
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