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：
8486040
负责人：
Christopher M Snyder
金额：
$ 7.75万
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/8486040
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.

描述（由申请人提供）：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，该细胞有效地延迟了肿瘤的进展并延长了整体患者的生存率。尽管经常刺激大量的肿瘤特异性T细胞，但仍未成功地尝试了几种疫苗接种策略。其中一些失败是可能是由于在肿瘤中起作用的主动免疫抑制机制。此外，很明显，T细胞运输和迁移到肿瘤将受到很大的影响根据刺激这些T细胞的条件。因此，理想的癌症疫苗将克服肿瘤的免疫抑制环境，并产生容易迁移到原发性肿瘤和转移酶的细胞。我们在这里认为，基于疱疹病毒巨细胞病毒（CMV）的持续疫苗载体可能会克服其中一些障碍。具体而言，持续的基于CMV的载体将不断增强肿瘤环境外的免疫系统，并产生T细胞，这些T细胞非常有效地迁移。我们以前的工作表明，CMV的安全，扩散缺陷的变体可以持续并刺激大型T细胞反应。我们对这种小赠款应用的目的是确定这种疫苗策略的潜力（或局限性）。为此，我们将使用新生成的高度相关的转移性黑色素瘤模型：突变体BRAF（BRAFV600E）表达的小鼠。 BRAF是一种丝氨酸/苏氨酸激酶，在约50％的人黑色素瘤中突变，BRAFV600E突变存在于约80％至90％的人Braf突变药物中。因此，该模型模仿了人类疾病。最令人兴奋的是，该模型使我们能够将BRAF抑制作用与疫苗接种相结合。这是一个非常重要的优势，因为BRAF抑制剂（例如最近获得FDA批准的vemurafenib）将在诊所中广泛使用，并且最近的数据表明vemurafenib可能会与免疫疗法协同作用。在这里，我们将在存在或不存在vemurafenib抑制BRAF的情况下测试基于CMV的疫苗接种的疗效，并具体侧重于肿瘤的T细胞浸润和功能。