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1.
Annu Rev Immunol ; 37: 173-200, 2019 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-30550719

RESUMEN

Malignant transformation of cells depends on accumulation of DNA damage. Over the past years we have learned that the T cell-based immune system frequently responds to the neoantigens that arise as a consequence of this DNA damage. Furthermore, recognition of neoantigens appears an important driver of the clinical activity of both T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapies. Here we review the evidence for the relevance of cancer neoantigens in tumor control and the biological properties of these antigens. We discuss recent technological advances utilized to identify neoantigens, and the T cells that recognize them, in individual patients. Finally, we discuss strategies that can be employed to exploit cancer neoantigens in clinical interventions.


Asunto(s)
Antígenos de Neoplasias/inmunología , Autoantígenos/inmunología , Vacunas contra el Cáncer/inmunología , Epítopos de Linfocito T/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias/inmunología , Linfocitos T/inmunología , Animales , Antígenos de Neoplasias/genética , Autoantígenos/genética , Epítopos de Linfocito T/genética , Humanos , Inmunidad Celular , Activación de Linfocitos , Medicina de Precisión , Linfocitos T/trasplante
2.
Cell ; 187(7): 1617-1635, 2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38552610

RESUMEN

The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of cancer patients. The development of personalized medicine represents a turning point and a new paradigm in cancer management, as biomarkers enable oncologists to tailor treatments based on the unique molecular profile of each patient's tumor. In this review, we discuss the scientific milestones of cancer biomarkers and explore future possibilities to improve the management of patients with solid tumors. This progress is primarily attributed to the biological characterization of cancers, advancements in testing methodologies, elucidation of the immune microenvironment, and the ability to profile circulating tumor fractions. Integrating these insights promises to continually advance the precision oncology field, fostering better patient outcomes.


Asunto(s)
Biomarcadores de Tumor , Neoplasias , Medicina de Precisión , Humanos , Oncología Médica/métodos , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Medicina de Precisión/métodos , Microambiente Tumoral
3.
Cell ; 187(7): 1636-1650, 2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38552611

RESUMEN

The precision oncology paradigm challenges the feasibility and data generalizability of traditional clinical trials. Consequently, an unmet need exists for practical approaches to test many subgroups, evaluate real-world drug value, and gather comprehensive, accessible datasets to validate novel biomarkers. Real-world data (RWD) are increasingly recognized to have the potential to fill this gap in research methodology. Established applications of RWD include informing disease epidemiology, pharmacovigilance, and healthcare quality assessment. Currently, concerns regarding RWD quality and comprehensiveness, privacy, and biases hamper their broader application. Nonetheless, RWD may play a pivotal role in supplementing clinical trials, enabling conditional reimbursement and accelerated drug access, and innovating trial conduct. Moreover, purpose-built RWD repositories may support the extension or refinement of drug indications and facilitate the discovery and validation of new biomarkers. This perspective explores the potential of leveraging RWD to advance oncology, highlights its benefits and challenges, and suggests a path forward in this evolving field.


Asunto(s)
Neoplasias , Humanos , Medicina de Precisión , Oncología Médica , Proyectos de Investigación , Biomarcadores
4.
Cell ; 186(8): 1755-1771, 2023 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-37059071

RESUMEN

A core mission of cancer genomics is to comprehensively chart molecular underpinnings of cancer-driving events and to provide personalized therapeutic strategies. Primarily focused on cancer cells, cancer genomics studies have successfully uncovered many drivers for major cancer types. Since the emergence of cancer immune evasion as a critical cancer hallmark, the paradigm has been elevated to the holistic tumor ecosystem, with distinct cellular components and their functional states elucidated. We highlight the milestones of cancer genomics, depict the evolving path of the field, and discuss future directions in completing the understanding of the tumor ecosystem and in advancing therapeutic strategies.


Asunto(s)
Neoplasias , Humanos , Genómica , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión
5.
Cell ; 185(10): 1619-1622, 2022 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-35561661

RESUMEN

Progress in studying sex as a biological variable (SABV) is slow, and the influence of gendered effects of the social environment on biology is largely unknown. Yet incorporating these concepts into basic science research will enhance our understanding of human health and disease. We provide steps to move this process forward.


Asunto(s)
Investigación Biomédica , Femenino , Humanos , Masculino , Medicina de Precisión , Caracteres Sexuales , Factores Sexuales , Salud de la Mujer
6.
Cell ; 185(1): 1-3, 2022 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-34995512

RESUMEN

Psychiatric disease is one of the greatest health challenges of our time. The pipeline for conceptually novel therapeutics remains low, in part because uncovering the biological mechanisms of psychiatric disease has been difficult. We asked experts researching different aspects of psychiatric disease: what do you see as the major urgent questions that need to be addressed? Where are the next frontiers, and what are the current hurdles to understanding the biological basis of psychiatric disease?


Asunto(s)
Antidepresivos/uso terapéutico , Ciencia de los Datos/métodos , Depresión/tratamiento farmacológico , Depresión/metabolismo , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Genómica/métodos , Medicina de Precisión/métodos , Investigación Biomédica Traslacional/métodos , Animales , Depresión/genética , Trastorno Depresivo/genética , Humanos , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Resultado del Tratamiento
7.
Nat Immunol ; 25(8): 1332-1343, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39009839

RESUMEN

Understanding the pathogenesis and clinical manifestations of systemic lupus erythematosus (SLE) has been a great challenge. Reductionist approaches to understand the nature of the disease have identified many pathogenetic contributors that parallel clinical heterogeneity. This Review outlines the immunological control of SLE and looks to experimental tools and approaches that are improving our understanding of the complex contribution of interacting genetics, environment, sex and immunoregulatory factors and their interface with processes inherent to tissue parenchymal cells. Efforts to advance precision medicine in the care of patients with SLE along with treatment strategies to correct the immune system hold hope and are also examined.


Asunto(s)
Lupus Eritematoso Sistémico , Lupus Eritematoso Sistémico/inmunología , Humanos , Animales , Medicina de Precisión , Predisposición Genética a la Enfermedad
8.
Nat Immunol ; 25(1): 19-28, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38168953

RESUMEN

Sepsis remains a major cause of morbidity and mortality in both low- and high-income countries. Antibiotic therapy and supportive care have significantly improved survival following sepsis in the twentieth century, but further progress has been challenging. Immunotherapy trials for sepsis, mainly aimed at suppressing the immune response, from the 1990s and 2000s, have largely failed, in part owing to unresolved patient heterogeneity in the underlying immune disbalance. The past decade has brought the promise to break this blockade through technological developments based on omics-based technologies and systems medicine that can provide a much larger data space to describe in greater detail the immune endotypes in sepsis. Patient stratification opens new avenues towards precision medicine approaches that aim to apply immunotherapies to sepsis, on the basis of precise biomarkers and molecular mechanisms defining specific immune endotypes. This approach has the potential to lead to the establishment of immunotherapy as a successful pillar in the treatment of sepsis for future generations.


Asunto(s)
Medicina de Precisión , Sepsis , Humanos , Sepsis/terapia , Inmunoterapia , Biomarcadores
9.
Cell ; 184(10): 2525-2531, 2021 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-33989545

RESUMEN

Human cell lines (CLs) are key assets for biomedicine but lack ancestral diversity. Here, we explore why genetic diversity among cell-based models is essential for making preclinical research more equitable and widely translatable. We lay out practical actions that can be taken to improve inclusivity in study design.


Asunto(s)
Investigación Biomédica/ética , Negro o Afroamericano/genética , Línea Celular , Medicina de Precisión/ética , Población Blanca/genética , Variación Genética , Humanos , Pruebas de Farmacogenómica
10.
Cell ; 184(6): 1415-1419, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33740447

RESUMEN

Precision medicine promises improved health by accounting for individual variability in genes, environment, and lifestyle. Precision medicine will continue to transform healthcare in the coming decade as it expands in key areas: huge cohorts, artificial intelligence (AI), routine clinical genomics, phenomics and environment, and returning value across diverse populations.


Asunto(s)
Atención a la Salud , Medicina de Precisión , Inteligencia Artificial , Macrodatos , Investigación Biomédica , Diversidad Cultural , Registros Electrónicos de Salud , Humanos , Fenómica
11.
Cell ; 184(7): 1661-1670, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33798439

RESUMEN

When it comes to precision oncology, proteogenomics may provide better prospects to the clinical characterization of tumors, help make a more accurate diagnosis of cancer, and improve treatment for patients with cancer. This perspective describes the significant contributions of The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium to precision oncology and makes the case that proteogenomics needs to be fully integrated into clinical trials and patient care in order for precision oncology to deliver the right cancer treatment to the right patient at the right dose and at the right time.


Asunto(s)
Neoplasias/diagnóstico , Proteogenómica/métodos , Bases de Datos Genéticas , Descubrimiento de Drogas , Estudios de Asociación Genética , Humanos , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión
12.
Cell ; 184(9): 2487-2502.e13, 2021 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-33857424

RESUMEN

Precision oncology has made significant advances, mainly by targeting actionable mutations in cancer driver genes. Aiming to expand treatment opportunities, recent studies have begun to explore the utility of tumor transcriptome to guide patient treatment. Here, we introduce SELECT (synthetic lethality and rescue-mediated precision oncology via the transcriptome), a precision oncology framework harnessing genetic interactions to predict patient response to cancer therapy from the tumor transcriptome. SELECT is tested on a broad collection of 35 published targeted and immunotherapy clinical trials from 10 different cancer types. It is predictive of patients' response in 80% of these clinical trials and in the recent multi-arm WINTHER trial. The predictive signatures and the code are made publicly available for academic use, laying a basis for future prospective clinical studies.


Asunto(s)
Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Medicina de Precisión , Mutaciones Letales Sintéticas , Transcriptoma/efectos de los fármacos , Anciano , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/inmunología , Ensayos Clínicos como Asunto , Femenino , Estudios de Seguimiento , Humanos , Inmunoterapia , Masculino , Neoplasias/genética , Neoplasias/patología , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de Supervivencia
13.
Cell ; 184(6): 1530-1544, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33675692

RESUMEN

The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.


Asunto(s)
COVID-19/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/terapia , Obesidad/epidemiología , Obesidad/terapia , Pandemias , Medicina de Precisión/métodos , SARS-CoV-2 , COVID-19/virología , Ritmo Circadiano , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigénesis Genética , Predisposición Genética a la Enfermedad , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Obesidad/genética , Obesidad/metabolismo , Prevalencia , Factores de Riesgo , Termotolerancia
14.
Cell ; 181(1): 92-101, 2020 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-32243801

RESUMEN

This Perspective explores the application of machine learning toward improved diagnosis and treatment. We outline a vision for how machine learning can transform three broad areas of biomedicine: clinical diagnostics, precision treatments, and health monitoring, where the goal is to maintain health through a range of diseases and the normal aging process. For each area, early instances of successful machine learning applications are discussed, as well as opportunities and challenges for machine learning. When these challenges are met, machine learning promises a future of rigorous, outcomes-based medicine with detection, diagnosis, and treatment strategies that are continuously adapted to individual and environmental differences.


Asunto(s)
Aprendizaje Automático , Medicina de Precisión , Humanos
15.
Cell ; 181(1): 208-208.e1, 2020 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-32243791

RESUMEN

Integrating precision diagnostics into personalized treatments requires understanding how biomarkers relate to clinical outcomes. Various clinical data collection methods exist, each with strengths and weaknesses. Interventional data are high quality but narrowly focused. Real-world data (RWD) provide broader information but with variable quality. Master protocols allow better efficiency in data collection. The master observational trial bridges the gap between interventional and retrospective RWD collection methods. To view this SnapShot, open or download the PDF.


Asunto(s)
Ensayos Clínicos como Asunto , Recolección de Datos , Medicina de Precisión , Humanos
16.
Cell ; 181(2): 236-249, 2020 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-32302568

RESUMEN

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral/fisiología , Atlas como Asunto , Transformación Celular Neoplásica/patología , Genómica/métodos , Humanos , Medicina de Precisión/métodos , Análisis de la Célula Individual/métodos
17.
Cell ; 180(1): 9-14, 2020 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-31951522

RESUMEN

This commentary introduces a new clinical trial construct, the Master Observational Trial (MOT), which hybridizes the power of molecularly based master interventional protocols with the breadth of real-world data. The MOT provides a clinical venue to allow molecular medicine to rapidly advance, answers questions that traditional interventional trials generally do not address, and seamlessly integrates with interventional trials in both diagnostic and therapeutic arenas. The result is a more comprehensive data collection ecosystem in precision medicine.


Asunto(s)
Estudios Observacionales como Asunto/métodos , Medicina de Precisión/métodos , Proyectos de Investigación/normas , Macrodatos , Protocolos de Ensayos Clínicos como Asunto , Humanos , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Estudios Observacionales como Asunto/normas
18.
Cell ; 183(2): 347-362.e24, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33064988

RESUMEN

Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).


Asunto(s)
Vacunas contra el Cáncer/inmunología , Inmunoterapia/métodos , Medicina de Precisión/métodos , Anciano , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Persona de Mediana Edad , Mutación , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunología
19.
Cell ; 181(7): 1661-1679.e22, 2020 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-32526207

RESUMEN

The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities. Dozens of drugs have been shown to be metabolized by single isolates from the gut microbiome, but the extent of this phenomenon is rarely explored in the context of microbial communities. Here, we develop a quantitative experimental framework for mapping the ability of the human gut microbiome to metabolize small molecule drugs: Microbiome-Derived Metabolism (MDM)-Screen. Included are a batch culturing system for sustained growth of subject-specific gut microbial communities, an ex vivo drug metabolism screen, and targeted and untargeted functional metagenomic screens to identify microbiome-encoded genes responsible for specific metabolic events. Our framework identifies novel drug-microbiome interactions that vary between individuals and demonstrates how the gut microbiome might be used in drug development and personalized medicine.


Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Microbioma Gastrointestinal/fisiología , Microbiota/efectos de los fármacos , Adulto , Animales , Bacterias/clasificación , Biomarcadores Farmacológicos/metabolismo , Heces/microbiología , Femenino , Microbioma Gastrointestinal/genética , Voluntarios Sanos , Humanos , Masculino , Metagenoma/genética , Metagenómica/métodos , Ratones , Ratones Endogámicos C57BL , Microbiota/genética , Preparaciones Farmacéuticas/metabolismo , Medicina de Precisión/métodos , ARN Ribosómico 16S/genética
20.
Annu Rev Biochem ; 88: 247-280, 2019 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-30901264

RESUMEN

The complexity of human cancer underlies its devastating clinical consequences. Drugs designed to target the genetic alterations that drive cancer have improved the outcome for many patients, but not the majority of them. Here, we review the genomic landscape of cancer, how genomic data can provide much more than a sum of its parts, and the approaches developed to identify and validate genomic alterations with potential therapeutic value. We highlight notable successes and pitfalls in predicting the value of potential therapeutic targets and discuss the use of multi-omic data to better understand cancer dependencies and drug sensitivity. We discuss how integrated approaches to collecting, curating, and sharing these large data sets might improve the identification and prioritization of cancer vulnerabilities as well as patient stratification within clinical trials. Finally, we outline how future approaches might improve the efficiency and speed of translating genomic data into clinically effective therapies and how the use of unbiased genome-wide information can identify novel predictive biomarkers that can be either simple or complex.


Asunto(s)
Genómica , Mutación , Neoplasias/tratamiento farmacológico , Humanos , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión
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