OV therapy induced changes in tumor secretome and their impact on therapy

OV疗法引起肿瘤分泌组的变化及其对治疗的影响

• 批准号: 9546233
• 负责人: Balveen Kaur
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9546233
• 关键词: Adult; Affect; Anaplastic astrocytoma; Animals; Anti-inflammatory; Antibodies; Antigen Presentation; Antigens; Antiviral Response; Attenuated; Autophagocytosis; Biological Response Modifier Therapy; Brain Neoplasms; CXCL12 gene; Central Nervous System Neoplasms; Cessation of life; Chemotaxis; Clinical Trials; Complex; Cross Presentation; Cytolysis; Cytoplasm; Dendritic Cells; Diagnosis; Disease; Dose; Endothelial Cells; Environment; Excision; Extracellular Space; Genes; Genetic Transcription; Glioblastoma; Global Change; Goals; HMGB1 Protein; Herpesvirus 1; Histones; Immune response; Immunotherapeutic agent; Immunotherapy; Infection; Infiltration; Inflammatory Response; Innate Immune Response; Interleukin-6; Intervention; Link; Luciferases; Macrophage Activation; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Measures; Mediating; Microglia; Modality; Molecular; Molecular Analysis; Natural Killer Cells; Nuclear Protein; Nucleosomes; Nude Mice; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Patients; Pattern; Primary Brain Neoplasms; Production; Proteins; Radiation; Recruitment Activity; Role; Serum; Stimulus; Stress; Structure; T-Lymphocyte; TNF gene; TP53 gene; Therapeutic; Tissues; Toxic effect; Translating; Tumor Biology; Viral; Virion; Virus; Virus Diseases; Virus Replication; adaptive immune response; angiogenesis; chemotherapy; combat; cytokine; defense response; design; expectation; extracellular; in vivo; macrophage; neoplastic; neoplastic cell; neutrophil; novel therapeutics; oncolysis; outcome forecast; personalized therapeutic; preclinical study; public health relevance; response; transcription factor; treatment strategy; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to evaluate the changes induced in the tumor microenvironment upon treatment with oncolytic viruses (OV) and assess how these changes impact OV therapy. These results will lead to a better understanding of OV therapy induced changes in tumor biology. OV treatment of tumors relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent no- neoplastic tissue. Results from clinical trials using replication competent OVs to treat patients with malignant gliomas have shown the new modality to be relatively safe, but high expectations of efficacy remain unmet (1, 2). The tumor's microenvironment is increasingly recognized as an important determinant for its progression and its response to therapeutics. We are investigating changes in the tumor microenvironment following oncolytic viral (OV) therapy, with the ultimate goal to devise better treatment strategies to combat brain tumors. In our preliminary studies, we have uncovered a significant increase in the release of HMGB1. HMGB1 is normally a cellular protein which is released into the extracellular environment upon certain stimuli and can serve as a damage associated molecular pattern. In this study we will evaluate the impact of this extracellular HMGB1 on tumor microenvironment, its impact on endothelial cells (Aim 1), macrophages (Aim 2) and antigen presentation to T cells (Aim 3).

描述（由申请方提供）：本提案的最终目标是评价溶瘤病毒（OV）治疗后肿瘤微环境中诱导的变化，并评估这些变化如何影响OV治疗。这些结果将导致更好地理解OV治疗诱导的肿瘤生物学变化。肿瘤的OV治疗依赖于病毒的癌症特异性复制，导致肿瘤破坏，对邻近的非肿瘤组织具有最小的毒性。使用可复制的OV治疗恶性胶质瘤患者的临床试验结果表明，新的模式相对安全，但对疗效的高期望仍未得到满足（1，2）。肿瘤的微环境越来越被认为是其进展及其对治疗反应的重要决定因素。我们正在研究溶瘤病毒（OV）治疗后肿瘤微环境的变化，最终目标是设计更好的治疗策略来对抗脑肿瘤。在我们的初步研究中，我们发现HMGB1的释放显着增加。HMGB1通常是一种细胞蛋白，在某些刺激下释放到细胞外环境中，并可作为损伤相关的分子模式。在这项研究中，我们将评估这种细胞外HMGB1对肿瘤微环境的影响，其对内皮细胞（Aim 1），巨噬细胞（Aim 2）和抗原呈递给T细胞（Aim 3）的影响。