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.

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，从而有效延缓肿瘤进展并延长患者总体生存期。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。其中一些失败是可能是由于肿瘤内运作的主动免疫抑制机制所致。此外，很明显，T 细胞运输和迁移到肿瘤中将受到严重影响这些 T 细胞受到刺激的条件。因此，理想的癌症疫苗将克服肿瘤的免疫抑制环境，并产生易于迁移到原发肿瘤和转移瘤中的细胞，无论它们在哪里。我们在此认为，基于疱疹病毒巨细胞病毒（CMV）传播缺陷版本的持久性疫苗载体可能会克服其中一些障碍。具体来说，基于 CMV 的持久载体将持续增强肿瘤环境之外的免疫系统，并产生能够高效进行全身迁移的 T 细胞。我们之前的工作表明，一种安全的、传播缺陷的 CMV 变体可以持续存在并刺激大量 T 细胞反应。我们申请这项小额赠款的目的是确定这种疫苗策略的潜力（或局限性）。为了实现这一目标，我们将使用新生成的高度相关的转移性黑色素瘤模型：诱导突变 BRAF (BRAFV600E) 表达的小鼠。 BRAF 是一种丝氨酸/苏氨酸激酶，在约 50% 的人类黑色素瘤中发生突变，而 BRAFV600E 突变存在于约 80% 至 90% 的人类 BRAF 突变黑色素瘤中。因此，该模型模拟了人类疾病。最令人兴奋的是，该模型使我们能够将 BRAF 抑制与疫苗接种结合起来。这是一个非常重要的优势，因为 BRAF 抑制剂，例如最近 FDA 批准的 Vemurafenib，将广泛用于临床，并且最近的数据表明 Vemurafenib 可能与免疫疗法产生协同作用。在这里，我们将测试在存在或不存在维莫非尼抑制 BRAF 的情况下基于 CMV 的疫苗接种的功效，特别关注肿瘤的 T 细胞浸润和肿瘤内的功能。