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

描述（由申请人提供）：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的总体生存期。已经尝试了几种疫苗接种策略，但没有成功，尽管经常刺激大量的肿瘤特异性T细胞。其中一些失败是 这可能是由于肿瘤内的主动免疫抑制机制。此外，已经变得明显的是，T细胞运输和迁移到肿瘤中将受到严重影响。 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，并产生容易迁移到原发性肿瘤和转移瘤中的细胞，无论它们在哪里。我们在这里认为，一个持久的疫苗载体，基于传播缺陷版本的疱疹病毒巨细胞病毒（CMV），可能会克服这些障碍。具体而言，持续的CMV载体将持续增强肿瘤环境外的免疫系统，并产生在全身迁移方面非常有效的T细胞。我们以前的工作表明，一种安全的，传播缺陷的CMV变体可以持续存在并刺激大的T细胞反应。我们申请这项小额资助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：小鼠中的突变BRAF（BRAFV 600 E）的表达被诱导。BRAF是一种丝氨酸/苏氨酸激酶，在约50%的人黑色素瘤中突变，BRAFV 600 E突变存在于约80 - 90%的人BRAF突变型黑色素瘤中。因此，该模型模拟人类疾病。最令人兴奋的是，这个模型使我们能够将联合收割机BRAF抑制与疫苗接种结合起来。这是一个很大的优势，因为BRAF抑制剂，如最近FDA批准的Vemurafenib，将广泛用于临床，最近的数据表明，Vemurafenib可能与免疫疗法协同作用。在这里，我们将测试在存在或不存在Vemurafenib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。

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.