Integrating NK and DC into Cancer Therapy

将 NK 和 DC 整合到癌症治疗中

基本信息

批准号：
7499879
负责人：
MICHAEL T LOTZE
金额：
$ 10.74万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-06 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7499879
关键词：
Acute Adam11 gene Adjuvant Adjuvant Therapy Adoptive Transfer Affinity American Society of Clinical Oncology Andro-Diane Animal Model Antigens Apoptosis Apoptotic Appearance Arsenic Attention Automobile Driving Bacteria Benign Prostatic Hypertrophy Bioinformatics Biological Biological Assay Biological Markers Biological Response Modifier Therapy Biology Biosensor Biostatistics Core Biotechnology Blood Blood Tests Breast Carcinoma CCL17 gene CCL18 gene CCL2 gene CCL22 gene CCL8 gene CD80 gene Cancer Biology Cancer Control Cancer Model Cancer Patient Cancer Therapy Evaluation Program Caring Carmustine/Cyclophosphamide/Melphalan/Prednisone/Vincristine Cell Therapy Cell physiology Cells Cellular Assay Cessation of life Charge China Chronic Chronic Disease Clinic Clinical Clinical Trials Colorectal Cancer Combined Modality Therapy Complex Containment Cross Presentation Cytokine Network Pathway Cytotoxic agent Data Dendritic Cells Depth Development Diagnosis Discrimination Disease Disease regression Distant Dose Early Diagnosis Effector Cell Elements End Point Endothelial Cells Engineering Environment Esophagitis Evaluation Event Extramural Activities Failure Family Family member Fibroblasts Frequencies Genes Genomics Glioma Goals Granzyme Head and neck structure Healed Hepatitis Human Human Genome Human Papillomavirus IL8 gene Image Immune Immune response Immunity Immunologics In Situ In Vitro Individual Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Ink Interferon-alpha Interleukin-1 Interleukin-10 Interleukin-12 Interleukin-13 Interleukin-16 Interleukin-17 Interleukin-2 Interleukin-4 Interleukin-6 Intralymphatic Injections Investigational Therapies Ions Laboratories Large Intestine Carcinoma Learning Left Lymphokines MHC antigen Malignant Lymph Node Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Mass Spectrum Analysis Measures Mediating Mediator of activation protein Memory Methods Minor Modeling Modification Molecular Monitor Mus Mutation Natural Killer Cells Nature Necrosis Neoplasm Metastasis Neoplasms Nitric Oxide Nuclear Numbers Outcome Patients Pattern Peptide/MHC Complex Peptides Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Physiologic pulse Play Pre-Clinical Model Primary carcinoma of the liver cells Principal Investigator Production Program Review Group Prostaglandins Proteins Proteomics Publishing Pulse taking Quality Control Randomized Recruitment Activity Rectal Cancer Recurrence Reporting Role Safety Scientist Seminal Sensitivity and Specificity Serum Serum Proteins Shared Paranoid Disorder Signal Transduction Site Smoke Societies Solutions Specificity Specimen Staging Standards of Weights and Measures Stimulus Supercomputing Suppressor-Effector T-Lymphocytes Surface System T-Lymphocyte TNF gene Techniques Technology Testing Tetradecanoylphorbol Acetate Therapeutic Time Tissues Today Toll-like receptors Toxic effect Toxin Treatment Protocols Treatment-Related Cancer Tumor Antigens Tumor Expansion Tumor Necrosis Factor Ligand Superfamily Member 6 Twin Multiple Birth United States Food and Drug Administration Universities University of Pittsburgh Cancer Institute Vaccines Virginia Virus Virus Diseases Week base biochip cancer care cancer therapy carcinogenesis chlorambucil/dactinomycin/methotrexate protocol contextual factors cost cost effective cytokine design expectation experience falls feeding healing human study improved in vivo insight interest interleukin-23 irradiation irritation kidney cell macrophage malignant breast neoplasm melanoma member neoplastic neoplastic cell neutrophil novel novel strategies outcome forecast perforin peripheral blood programs prospective response success surface enhanced laser desorption ionization theories tumor tumor growth tumor progression vaccination strategy

项目摘要

DCs, NK and T-cells found within human tumors have been associated with an improved prognosis in almost every tumor type examined. Indeed their recruitment may be modified during development of the chronic inflammatory response. Cancer arises in the setting of chronic inflammation - inducing an acute inflammatory response to elicit new T-cells capable of mediating sustained and more effective antitumor activity is the central premise of this proposal. Integrating NK and DC into Cancer Therapy with direct injection into tumor or coincubated ex vivo with tumor or tumor antigens administered as an immunogen, will result in tumor destruction and elicit an effective adaptive immune response. The identification of critical biomarkers and surrogates using modern proteomic, genomic, and cellomic strategies will be integrated into all projects as a means to test these strategies more readily in early disease. We hypothesize that by directing NK and DC to rumor sites in situ, that we can enhance regression of established local disease, promoting a more effective systemic immunity to tumor. Coordinate signaling is necessary between NK and DCs to initiate optimal TH1 polarization, subsequently driving an effective adaptive T-cell response to cancer. Indeed, after two decades of NKJANK/LAK adoptive transfer and several years of experience with over 1000 patients receiving DCs, it is becoming apparent that cooperative interactions between NK and DC will be necessary to modify the established immune response to cancer. We will investigate this in four projects: Project I. Initiating the Adaptive Immune Response to Cancer; Project II. NK cells induce DCl-mediated anti-rumor immunity, and Project IlL IL-1 Homolognes Promote the Acute Inflammatory Response to Melanoma. Development of these three projects will be supported by three cores: A) Administrative, Bioinformatics and Biostatistics Core B) Imaging Core, and C) Proteomics Core. Project I will enable further development of the clinical trials proposed in patients with melanoma and colorectal cancer who will be evaluated and treated in Projects II and III. Evaluation of direct intralymphatic injection of NK matured DC 1 fed tumor antigen or lysates will be contrasted with strategies using direct intratumoral injection of NK and DC.

人类肿瘤中发现的 DC、NK 和 T 细胞几乎与改善预后相关检查的每种肿瘤类型。事实上，在慢性疾病的发展过程中，它们的募集可能会发生改变。炎症反应。癌症发生在慢性炎症的背景下——诱发急性炎症诱导新 T 细胞能够介导持续且更有效的抗肿瘤活性的反应是核心本提案的前提。通过直接注射到肿瘤或将 NK 和 DC 整合到癌症治疗中与作为免疫原施用的肿瘤或肿瘤抗原离体共孵育，将导致肿瘤破坏并引发有效的适应性免疫反应。关键生物标志物的鉴定和使用现代蛋白质组学、基因组学和细胞组学策略的替代品将作为意味着在疾病早期更容易测试这些策略。我们假设通过引导 NK 和 DC 谣言地点就地，我们可以增强已确定的局部疾病的消退，促进更有效的治疗对肿瘤的全身免疫。 NK 和 DC 之间需要协调信号传导以启动最佳 TH1 极化，随后驱动有效的适应性 T 细胞对癌症的反应。确实，经过二十年 NKJANK/LAK 过继转移和数年超过 1000 例接受 DC 患者的经验，越来越明显的是，NK 和 DC 之间的合作互动对于改变建立了针对癌症的免疫反应。我们将在四个项目中对此进行调查：项目 I. 启动对癌症的适应性免疫反应；项目二。 NK 细胞诱导 DCl 介导的抗肿瘤免疫，并且 IlL 项目 IL-1 同源物促进黑色素瘤的急性炎症反应。发展这三个项目将得到三个核心的支持：A) 行政、生物信息学和生物统计学核心 B) 成像核心，以及 C) 蛋白质组学核心。项目 I 将促进临床试验的进一步发展提议在黑色素瘤和结直肠癌患者中进行评估和治疗，这些患者将在项目 II 和三．直接淋巴内注射 NK 成熟 DC 1 饲喂肿瘤抗原或裂解物的评价将与直接瘤内注射 NK 和 DC 的策略形成对比。