RESUMEN
The analysis of big healthcare data has enormous potential as a tool for advancing oncology drug development and patient treatment, particularly in the context of precision medicine. However, there are challenges in organizing, sharing, integrating, and making these data readily accessible to the research community. This review presents five case studies illustrating various successful approaches to addressing such challenges. These efforts are CancerLinQ, the American Association for Cancer Research Project GENIE, Project Data Sphere, the National Cancer Institute Genomic Data Commons, and the Veterans Health Administration Clinical Data Initiative. Critical factors in the development of these systems include attention to the use of robust pipelines for data aggregation, common data models, data deidentification to enable multiple uses, integration of data collection into physician workflows, terminology standardization and attention to interoperability, extensive quality assurance and quality control activity, incorporation of multiple data types, and understanding how data resources can be best applied. By describing some of the emerging resources, we hope to inspire consideration of the secondary use of such data at the earliest possible step to ensure the proper sharing of data in order to generate insights that advance the understanding and the treatment of cancer.
Asunto(s)
Macrodatos , Neoplasias , Humanos , Estados Unidos/epidemiología , Neoplasias/genética , Neoplasias/terapia , Oncología Médica , Atención a la SaludRESUMEN
Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia/efectos adversos , Enfermedades del Sistema Nervioso/diagnóstico , Guías de Práctica Clínica como Asunto , Consenso , Humanos , Enfermedades del Sistema Nervioso/inducido químicamente , Enfermedades del Sistema Nervioso/inmunología , Neurólogos/estadística & datos numéricos , Oncólogos/estadística & datos numéricos , Grupo de Atención al Paciente/organización & administración , Grupo de Atención al Paciente/estadística & datos numéricosRESUMEN
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, improving outcomes in patients with advanced malignancies. The use of ICIs in clinical practice, and the number of ICI clinical trials, are rapidly increasing. The use of ICIs in combination with other forms of cancer therapy, such as chemotherapy, radiotherapy, or targeted therapy, is also expanding. However, immune-related adverse events (irAEs) can be serious in up to a third of patients. Critical questions remain surrounding the characteristics and outcomes of irAEs, and how they may affect the overall risk-benefit relationship for combination therapies. This article proposes a framework for irAE classification and reporting, and identifies limitations in the capture and sharing of data on irAEs from current clinical trial and real-world data. We outline key gaps and suggestions for clinicians, clinical investigators, drug sponsors, patients, and other stakeholders to make these critical data more available to researchers for pooled analysis, to advance contemporary understanding of irAEs, and ultimately improve the efficacy of ICIs.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/complicaciones , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
We recently reported the development of a fully-human, CD3-binding bispecific antibody for immunotherapy of malignant glioma. To translate this therapeutic (hEGFRvIII-CD3- bi-scFv) to clinical trials and to help further the translation of other similar CD3-binding therapeutics, some of which are associated with neurologic toxicities, we performed a good laboratory practice (GLP) toxicity study to assess for potential behavioral, chemical, hematologic, and pathologic toxicities including evaluation for experimental autoimmune encephalomyelitis (EAE). To perform this study, male and female C57/BL6 mice heterozygous for the human CD3 transgene (20/sex) were allocated to one of four designated groups. All animals were administered one dose level of hEGFRvIII-CD3 bi-scFv or vehicle control. Test groups were monitored for feed consumption, changes in body weight, and behavioral disturbances including signs of EAE. Urinalysis, hematologic, and clinical chemistry analysis were also performed. Vehicle and test chemical-treated groups were humanely euthanized 48 hours or 14 days following dose administration. Complete gross necropsy of all tissues was performed, and selected tissues plus all observed gross lesions were collected and evaluated for microscopic changes. This included hematoxylin-eosin histopathological evaluation and Fe-ECR staining for myelin sheath enumeration. There were no abnormal clinical observations or signs of EAE noted during the study. There were no statistical changes in food consumption, body weight gain, or final body weight among groups exposed to hEGFRvIII-CD3 bi-scFv compared to the control groups for the 2- and 14-day timepoints. There were statistical differences in some clinical chemistry, hematologic and urinalysis endpoints, primarily in the females at the 14-day timepoint (hematocrit, calcium, phosphorous, and total protein). No pathological findings related to hEGFRvIII-CD3 bi-scFv administration were observed. A number of gross and microscopic observations were noted but all were considered to be incidental background findings. The results of this study allow for further translation of this and other important CD3 modulating bispecific antibodies.
Asunto(s)
Anticuerpos Biespecíficos/farmacología , Complejo CD3/inmunología , Receptores ErbB/inmunología , Glioma/inmunología , Animales , Anticuerpos Biespecíficos/inmunología , Peso Corporal/efectos de los fármacos , Peso Corporal/inmunología , Complejo CD3/farmacología , Modelos Animales de Enfermedad , Receptores ErbB/farmacología , Femenino , Glioma/patología , Glioma/terapia , Humanos , Inmunoterapia/efectos adversos , Masculino , Ratones , Anticuerpos de Cadena Única/inmunología , Anticuerpos de Cadena Única/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: First-in-human (FIH) clinical trials require careful selection of a safe yet biologically relevant starting dose. Typically, such starting doses are selected based on toxicity studies in a pharmacologically relevant animal model. However, with the advent of target-specific and highly active immunotherapeutics, both the Food and Drug Administration and the European Medicines Agency have provided guidance that recommend determining a safe starting dose based on a minimum anticipated biological effect level (MABEL) approach. METHODS: We recently developed a T cell activating bispecific antibody that effectively treats orthotopic patient-derived malignant glioma and syngeneic glioblastoma in mice (hEGFRvIII:CD3 bi-scFv). hEGFRvIII:CD3 bi-scFv is comprized of two single chain antibody fragments (bi-scFvs) that bind mutant epidermal growth factor receptor variant III (EGFRvIII), a mutation frequently seen in malignant glioma, and human CD3ε on T cells, respectively. In order to establish a FIH dose, we used a MABEL approach to select a safe starting dose for hEGFRvIII:CD3 bi-scFv, based on a combination of in vitro data, in vivo animal studies, and theoretical human receptor occupancy modeling. RESULTS: Using the most conservative approach to the MABEL assessment, a dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/kg body weight was selected as a safe starting dose for a FIH clinical study. CONCLUSIONS: The comparison of our MABEL-based starting dose to our in vivo efficacious dose and the theoretical human receptor occupancy strongly supports that our human starting dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/patient kg will be safe.
Asunto(s)
Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Complejo CD3/inmunología , Receptores ErbB/inmunología , Glioma/tratamiento farmacológico , Modelos Teóricos , Animales , Apoptosis , Proliferación Celular , Simulación por Computador , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Evaluación Preclínica de Medicamentos , Femenino , Glioma/inmunología , Glioma/patología , Humanos , Ratones , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Bispecific single chain antibody fragments (bi-scFv) represent an emerging class of biotherapeutics. We recently developed a fully human bi-scFv (EGFRvIII:CD3 bi-scFv) with the goal of redirecting CD3-expressing T cells to recognize and destroy malignant, EGFRvIII-expressing glioma. In mice, we showed that EGFRvIII:CD3 bi-scFv effectively treats orthotopic patient-derived malignant glioma and syngeneic glioblastoma. Here, we developed a targeted assay for pharmacokinetic (PK) analysis of EGFRvIII:CD3 bi-scFv, a necessary step in the drug development process. Using microflow liquid chromatography coupled to a high resolution parallel reaction monitoring mass spectrometry, and data analysis in Skyline, we developed a bottom-up proteomic assay for quantification of EGFRvIII:CD3 bi-scFv in both plasma and whole blood. Importantly, a protein calibrator, along with stable isotope-labeled EGFRvIII:CD3 bi-scFv protein, were used for absolute quantification. A PK analysis in a CD3 humanized mouse revealed that EGFRvIII:CD3 bi-scFv in plasma and whole blood has an initial half-life of â¼8 min and a terminal half-life of â¼2.5 h. Our results establish a sensitive, high-throughput assay for direct quantification of EGFRvIII:CD3 bi-scFv without the need for immunoaffinity enrichment. Moreover, these pharmacokinetic parameters will guide drug optimization and dosing regimens in future IND-enabling and phase I studies of EGFRvIII:CD3 bi-scFv.
Asunto(s)
Anticuerpos Biespecíficos/sangre , Complejo CD3/sangre , Receptores ErbB/sangre , Glioblastoma/sangre , Animales , Anticuerpos Biespecíficos/farmacocinética , Anticuerpos Biespecíficos/uso terapéutico , Complejo CD3/farmacocinética , Complejo CD3/uso terapéutico , Línea Celular Tumoral , Cromatografía Liquida , Receptores ErbB/farmacocinética , Receptores ErbB/uso terapéutico , Glioblastoma/inmunología , Glioblastoma/terapia , Humanos , Espectrometría de Masas , Ratones , Proteómica/métodos , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Purpose: Conventional therapy for malignant glioma fails to specifically target tumor cells. In contrast, substantial evidence indicates that if appropriately redirected, T cells can precisely eradicate tumors. Here we report the rational development of a fully human bispecific antibody (hEGFRvIII-CD3 bi-scFv) that redirects human T cells to lyse malignant glioma expressing a tumor-specific mutation of the EGFR (EGFRvIII).Experimental Design: We generated a panel of bispecific single-chain variable fragments and optimized design through successive rounds of screening and refinement. We tested the ability of our lead construct to redirect naïve T cells and induce target cell-specific lysis. To test for efficacy, we evaluated tumor growth and survival in xenogeneic and syngeneic models of glioma. Tumor penetrance following intravenous drug administration was assessed in highly invasive, orthotopic glioma models.Results: A highly expressed bispecific antibody with specificity to CD3 and EGFRvIII was generated (hEGFRvIII-CD3 bi-scFv). Antibody-induced T-cell activation, secretion of proinflammatory cytokines, and proliferation was robust and occurred exclusively in the presence of target antigen. hEGFRvIII-CD3 bi-scFv was potent and target-specific, mediating significant lysis of multiple malignant glioma cell lines and patient-derived malignant glioma samples that heterogeneously express EGFRvIII. In both subcutaneous and orthotopic models, well-engrafted, patient-derived malignant glioma was effectively treated despite heterogeneity of EGFRvIII expression; intravenous hEGFRvIII-CD3 bi-scFv administration caused significant regression of tumor burden (P < 0.0001) and significantly extended survival (P < 0.0001). Similar efficacy was obtained in highly infiltrative, syngeneic glioma models, and intravenously administered hEGFRvIII-CD3 bi-scFv localized to these orthotopic tumors.Conclusions: We have developed a clinically translatable bispecific antibody that redirects human T cells to safely and effectively treat malignant glioma. On the basis of these results, we have developed a clinical study of hEGFRvIII-CD3 bi-scFv for patients with EGFRvIII-positive malignant glioma. Clin Cancer Res; 24(15); 3611-31. ©2018 AACR.
Asunto(s)
Complejo CD3/antagonistas & inhibidores , Receptores ErbB/antagonistas & inhibidores , Glioma/tratamiento farmacológico , Inmunoterapia , Animales , Anticuerpos Biespecíficos/farmacología , Complejo CD3/inmunología , Línea Celular Tumoral , Receptores ErbB/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Glioma/inmunología , Glioma/patología , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Ratones , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Anticuerpos de Cadena Única/inmunología , Anticuerpos de Cadena Única/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: Immunotherapy embodies any approach that manipulates the immune system for therapeutic benefit. In this regard, various clinical trials have employed direct vaccination with patient-specific dendritic cells or adoptive T cell therapy to target highly aggressive tumors. Both modalities have demonstrated great specificity, an advantage that is unmatched by other treatment strategies. However, their full potential has yet to be realized. Areas covered: In this review, we provide an overview of chemokines in pathogen and anti-tumor immune responses and discuss further improving immunotherapies by arming particular chemokine axes. Expert commentary: The chemokine macrophage inflammatory protein-1 alpha (MIP-1α, CCL3) has emerged as a potent activator of both innate and adaptive responses. Specifically, CCL3 plays a critical role in recruiting distinct immune phenotypes to intratumoral sites, is a pivotal player in regulating lymph node homing of dendritic cell subsets, and induces antigen-specific T cell responses. The recent breadth of literature outlines the various interactions of CCL3 with these cellular subsets, which have now served as a basis for immunotherapeutic translation.
Asunto(s)
Adyuvantes Inmunológicos , Quimiocina CCL3/inmunología , Quimiocinas/inmunología , Células Dendríticas/inmunología , Inmunoterapia Adoptiva/métodos , Infecciones/terapia , Neoplasias/terapia , Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , Células Dendríticas/trasplante , Humanos , Inmunidad Innata , Infecciones/inmunología , Neoplasias/inmunología , Linfocitos T/trasplanteRESUMEN
INTRODUCTION: Glioblastoma is the most common primary brain tumor in adults and prognosis remains poor with a median survival of approximately 15-17 months. This review provides an overview of recent advances in the field of glioblastoma immunotherapy. Areas covered: Recent advances in dendritic cell vaccination immunotherapy are showing encouraging results in clinical trials and promise to extend patient survival. In this report we discuss current scientific knowledge regarding dendritic cell (DC) vaccines, including approaches to differentiating, priming, and injecting dendritic cells to achieve maximal anti-tumor efficacy in glioblastoma. These findings are compared to recently completed and currently ongoing glioblastoma clinical trials. Novel methods such as 'fastDCs' and vaccines targeting DCs in-vivo may offer more effective treatment when compared to traditional DC vaccines and have already entered the clinic. Expert commentary: Finally, we discuss the challenges of T-cell dysfunctions caused by glioblastoma immunosuppression and how they affect dendritic cell vaccinations approaches.