A New Anti-CD27 Monoclonal Antibody Adjuvant for Pancreatic Cancer Vaccines

描述（由申请人提供）：蛋白质疫苗的免疫原性较弱，但我们已经开始通过针对树突状细胞（DC）上摄取受体的单克隆抗体靶向胰腺癌蛋白来克服这一障碍。我们强调交叉呈现活跃的dc，如DEC-205+ dc。从包括我们自己的实验室在内的许多实验室的研究来看，CD70——CD27的肿瘤坏死因子家族配体——现在被认为是启动T细胞免疫、肿瘤中T细胞积累和T细胞长期存活的主要因素。CD70在dc上的表达受到严格控制，但CD27总是在na - ve T细胞上表达。我们假设，通过确保CD70信号的传递，激动性抗cd27抗体将成为提高胰腺癌疫苗疗效的优越佐剂。这可以用新的可用工具来解决。我们建议探索一种新的针对huCD27的全人单抗，作为dc靶向胰腺癌蛋白疫苗更有效的佐剂。我们还将使用人类CD27转基因小鼠模型，这两种新工具都是由Celldex Therapeutics开发的。为了获得原理证明，我们将首先将抗cd27与一种异种胰腺抗原、人间皮素、HuMSLN联合使用，靶向于anti-DEC-205 mAb。我们将评估T细胞免疫的数量、质量和持续时间。抗cd27还将与聚IC和激动性抗cd40的组合进行比较，后者是已知最强大的dc上CD70表达诱导剂。接下来，我们将使用稳定转导表达huMSLN的胰腺可移植肿瘤Panc02来评估抗cd27在预防和治疗方案中的功效。在一个更具挑战性的环境中，我们将测试人类抗hud27是否能有效地指导小鼠克服对自身/小鼠间皮素的自我耐受。我们主要想确定允许T细胞免疫进入肿瘤微环境并发挥作用的疫苗条件。总之，我们的研究计划将开辟一个新的领域，以提高对大多数胰腺癌表达的胰腺癌抗原-间皮素的疫苗接种。这一建议的影响不仅是为人类开辟了抗cd27的途径，并为胰腺癌带来了一种易于耐受的dc靶向蛋白疫苗方法，而且还扩大了胰腺癌免疫评估的范围，在CD4+和CD8+ T细胞特性，特别是持久性和进入可移植肿瘤的水平上。如果抗cd27如假设的那样被证明是一种综合和持久的T细胞免疫的优越佐剂，这些临床前研究的所有组成部分都将在该提议提出后的2年内迅速进入临床试验。

DESCRIPTION (provided by applicant): Protein vaccines have suffered from weak immunogenicity but we have begun to overcome this obstacle by targeting pancreatic cancer proteins within monoclonal antibodies to uptake receptors on dendritic cells (DC). We emphasize DCs active in cross presentation such as DEC-205+ DCs. From research in many labs including our own, CD70 -- the tumor necrosis factor family ligand for CD27 -- is now appreciated to be a major contributor for initiating T cell immunity, accumulation of T cells in te tumor, and long term T cell survival. The expression of CD70 on DCs is tightly controlled, but CD27 is always expressed on na¿ve T cells. We hypothesize that agonistic anti-CD27 antibody will be a superior adjuvant to improve the efficacy of pancreatic cancer vaccines, by ensuring delivery of the CD70 signal. This can be approached with new available tools. We propose to explore a new fully human Mab against huCD27 as a more effective adjuvant for a DC-targeted pancreatic cancer protein vaccine. We will also use a human CD27 transgenic mouse model, with both of these new tools being developed by Celldex Therapeutics. To obtain proof-of-principle, we will first use anti-CD27 in combination with a xenogenic pancreatic antigen, human mesothelin, HuMSLN, targeted within anti-DEC-205 mAb. We will assess the quantity, quality and duration of T cell immunity. Anti-CD27 will also be compared to the combination of poly IC and agonistic anti-CD40, a combination that is the most powerful known inducer of CD70 expression on DCs. We will next assess the efficacy of anti-CD27 in both prophylactic and therapeutic protocols using the Panc02 pancreatic transplantable tumor that is stably transduced to express huMSLN. In a more challenging setting, we will test if human anti-huCD27 can efficiently instruct mice to overcome self-tolerance to self/mouse mesothelin. We mainly want to identify vaccine conditions that allow T cell immunity to enter and function in the tumor microenvironment. In summary, our research plan will open up a new field to improve vaccination to a pancreatic cancer antigen, mesothelin, expressed by most pancreatic cancers. The impact of this proposal is not only to open up the anti-CD27 approach for humans, and to bring a readily tolerated DC-targeted protein vaccine approach to pancreatic cancer, but also to expand the scope of pancreatic cancer immune evaluation, at the level of CD4+ and CD8+ T cell properties especially durability and entry into transplantable tumors. All components of these preclinical studies are designed to be brought into clinical testing quickly, within the 2 years of this proposal, if anti-CD27 as hypothesized proves to be a superior adjuvant for integrated and durable T cell immunity.