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Synergy between BRAF inhibition, tumor-localized T cells and a persistent vaccine

BRAF 抑制、肿瘤定位 T 细胞和持久性疫苗之间的协同作用

基本信息

批准号：
8635992
负责人：
Christopher M Snyder
金额：
$ 7.52万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635992
关键词：
Adverse effects Affect Alleles Antibodies Antigens Applications Grants BRAF gene Blocking Antibodies Cancer Vaccines Cell physiology Cells Clinic Clinical Trials Cytomegalovirus Data Development Disease Economic Inflation Environment FDA approved Failure Functional disorder Generations Genome Goals Herpesviridae Human Immune Immune response Immune system Immunity Immunosuppression Immunotherapy In Vitro Infiltration Lung Lytic Maintenance Malignant Neoplasms Measures Memory Metastatic Melanoma Modeling Mus Mutate Mutation Neoplasm Metastasis Organ PTEN gene Pathology Pathway interactions Patients Pattern Penetrance Population Primary Neoplasm Production Protein-Serine-Threonine Kinases Proto-Oncogene Proteins B-raf Recombinants Route Signal Transduction Source T cell response T-Cell Proliferation T-Lymphocyte Testing Time Tumor Suppressor Proteins Vaccinated Vaccination Vaccines Vaccinia virus Variant Work abstracting base cell motility cytokine efficacy testing exhaustion human disease immunogenic in vivo inhibitor/antagonist latent persistent infection lymph nodes melanoma migration mucosal site mutant neoplastic cell public health relevance response success trafficking tumor tumor progression vaccination strategy vaccine evaluation vector vector vaccine vector-based vaccine

项目摘要

DESCRIPTION (provided by applicant): Abstract: A long-standing goal for melanoma immune therapy is the induction of tumor-specific T cells that effectively delay tumor progression and prolong overall patient survival. Several vaccination strategies have been attempted without success, despite often stimulating large numbers of tumor-specific T cells. Some of this failure is likely due to the active immune suppression mechanisms that operate within tumors. Moreover, it has become apparent that T cell trafficking and migration into tumors will be heavily influenced by the conditions in which those T cells were stimulated. Thus, the ideal cancer vaccine would overcome the immune suppressive environment of the tumor and produce cells that readily migrate into the primary tumor and metastases, wherever they may be. We argue here that a persistent vaccine vector, based on a spread- defective version of the herpes virus cytomegalovirus (CMV), may overcome some of these obstacles. Specifically, persistent CMV-based vectors will continuously boost the immune system outside of the tumor environment and produce T cells that are highly effective at migrating systemically. Our previous work demonstrated that a safe, spread-defective variant of CMV could persist and stimulate large T cell responses. Our aim for this small grant application is to determine the potential for (or limitations of) such a vaccine strategy. To accomplish this, we will use a newly generated, highly relevant model of metastatic melanoma: mice in which expression of a mutant BRAF (BRAFV600E) is induced. BRAF is a serine/threonine kinase that is mutated in ~50% of human melanomas and the BRAFV600E mutation is present in ~80 to 90% of human BRAF-mutant melanomas. Thus, this model mimics human disease. Most excitingly, this model enables us to combine BRAF inhibition with vaccination. This is a great advantage important because BRAF inhibitors, such as the recently FDA approved Vemurafenib, will be widely used in the clinic and recent data suggest that Vemurafenib may synergize with immune therapies. Here we will test the efficacy of CMV-based vaccination in the presence or absence of Vemurafenib inhibition of BRAF, with specific focus on T cell infiltration of tumors and function within tumors.

摘要：黑色素瘤免疫治疗的长期目标是诱导肿瘤特异性T细胞，有效延缓肿瘤进展并延长患者的总体生存期。尽管经常刺激大量肿瘤特异性T细胞，但已经尝试了几种疫苗接种策略，但没有成功。有些失败是