RESUMO
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.
Assuntos
Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/genética , Autoantígenos/genética , Epitopos de Linfócito T/genética , Humanos , Imunidade Celular , Ativação Linfocitária , Medicina de Precisão , Linfócitos T/transplanteRESUMO
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.
Assuntos
Biomarcadores Tumorais , Neoplasias , Medicina de Precisão , Humanos , Oncologia/métodos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Medicina de Precisão/métodos , Microambiente TumoralRESUMO
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.
Assuntos
Neoplasias , Humanos , Medicina de Precisão , Oncologia , Projetos de Pesquisa , BiomarcadoresRESUMO
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.
Assuntos
Neoplasias , Humanos , Genômica , Neoplasias/genética , Neoplasias/terapia , Medicina de PrecisãoRESUMO
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.
Assuntos
Pesquisa Biomédica , Feminino , Humanos , Masculino , Medicina de Precisão , Caracteres Sexuais , Fatores Sexuais , Saúde da MulherRESUMO
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?
Assuntos
Antidepressivos/uso terapêutico , Ciência de Dados/métodos , Depressão/tratamento farmacológico , Depressão/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Genômica/métodos , Medicina de Precisão/métodos , Pesquisa Translacional Biomédica/métodos , Animais , Depressão/genética , Transtorno Depressivo/genética , Humanos , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Resultado do TratamentoRESUMO
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.
Assuntos
Lúpus Eritematoso Sistêmico , Lúpus Eritematoso Sistêmico/imunologia , Humanos , Animais , Medicina de Precisão , Predisposição Genética para DoençaRESUMO
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.
Assuntos
Medicina de Precisão , Sepse , Humanos , Sepse/terapia , Imunoterapia , BiomarcadoresRESUMO
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.
Assuntos
Pesquisa Biomédica/ética , Negro ou Afro-Americano/genética , Linhagem Celular , Medicina de Precisão/ética , População Branca/genética , Variação Genética , Humanos , Testes FarmacogenômicosRESUMO
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.
Assuntos
Atenção à Saúde , Medicina de Precisão , Inteligência Artificial , Big Data , Pesquisa Biomédica , Diversidade Cultural , Registros Eletrônicos de Saúde , Humanos , FenômicaRESUMO
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.
Assuntos
Neoplasias/diagnóstico , Proteogenômica/métodos , Bases de Dados Genéticas , Descoberta de Drogas , Estudos de Associação Genética , Humanos , Neoplasias/genética , Neoplasias/terapia , Medicina de PrecisãoRESUMO
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.
Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Medicina de Precisão , Mutações Sintéticas Letais , Transcriptoma/efeitos dos fármacos , Idoso , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/imunologia , Ensaios Clínicos como Assunto , Feminino , Seguimentos , Humanos , Imunoterapia , Masculino , Neoplasias/genética , Neoplasias/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
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.
Assuntos
COVID-19/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Obesidade/epidemiologia , Obesidade/terapia , Pandemias , Medicina de Precisão/métodos , SARS-CoV-2 , COVID-19/virologia , Ritmo Circadiano , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética , Predisposição Genética para Doença , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Obesidade/genética , Obesidade/metabolismo , Prevalência , Fatores de Risco , TermotolerânciaRESUMO
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.
Assuntos
Aprendizado de Máquina , Medicina de Precisão , HumanosRESUMO
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.
Assuntos
Ensaios Clínicos como Assunto , Coleta de Dados , Medicina de Precisão , HumanosRESUMO
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.
Assuntos
Transformação Celular Neoplásica/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral/fisiologia , Atlas como Assunto , Transformação Celular Neoplásica/patologia , Genômica/métodos , Humanos , Medicina de Precisão/métodos , Análise de Célula Única/métodosRESUMO
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.
Assuntos
Estudos Observacionais como Assunto/métodos , Medicina de Precisão/métodos , Projetos de Pesquisa/normas , Big Data , Protocolos de Ensaio Clínico como Assunto , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Estudos Observacionais como Assunto/normasRESUMO
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).
Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Medicina de Precisão/métodos , Idoso , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Pessoa de Meia-Idade , Mutação , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologiaRESUMO
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.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Microbioma Gastrointestinal/fisiologia , Microbiota/efeitos dos fármacos , Adulto , Animais , Bactérias/classificação , Biomarcadores Farmacológicos/metabolismo , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Voluntários Saudáveis , Humanos , Masculino , Metagenoma/genética , Metagenômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/genética , Preparações Farmacêuticas/metabolismo , Medicina de Precisão/métodos , RNA Ribossômico 16S/genéticaRESUMO
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.