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

描述(申请人提供)：摘要：黑色素瘤免疫治疗的一个长期目标是诱导肿瘤特异性T细胞，有效地延缓肿瘤进展并延长患者总体生存时间。尽管经常刺激大量的肿瘤特异性T细胞，但已经尝试了几种疫苗接种策略，但都没有成功。这种失败的部分原因是 可能是由于在肿瘤内运作的主动免疫抑制机制所致。此外，很明显，T细胞的运输和向肿瘤的迁移将受到严重影响 根据这些T细胞被刺激的条件。因此，理想的癌症疫苗将克服肿瘤的免疫抑制环境，产生容易迁移到原发肿瘤和转移瘤的细胞，无论它们在哪里。我们在这里认为，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的一些障碍。具体地说，基于CMV的持久性载体将持续增强肿瘤环境外的免疫系统，并产生在系统内高效迁移的T细胞。我们之前的工作证明，一种安全的、传播缺陷的CMV变种可以持续存在并刺激大的T细胞反应。我们申请这笔小额赠款的目的是确定这种疫苗策略的潜力(或局限性)。为了做到这一点，我们将使用一个新产生的高度相关的转移性黑色素瘤模型：在其中诱导突变的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突变在约80%至90%的人类BRAF突变黑色素瘤中存在。因此，这个模型模拟了人类疾病。最令人兴奋的是，这个模型使我们能够将抑制BRAF与接种疫苗结合起来。这是一个非常重要的优势，因为BRAF抑制剂，如最近FDA批准的Vemurafenib，将在临床上广泛使用，最近的数据表明Vemurafenib可能与免疫治疗协同作用。在这里，我们将测试基于CMV的疫苗在有或没有Vemurafenib抑制BRAF的情况下的效果，特别关注肿瘤中T细胞的渗透和肿瘤内的功能。

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.