CD40 and TLR Agonists in Melanoma

描述（由申请人提供）：我们在分子水平上对T细胞活化的理解的进展已经允许在癌症患者中操纵T细胞调节。参与T细胞调节的重要分子是在抗原呈递细胞和B细胞上表达的CD 40。CD 40-CD 40配体相互作用是产生T细胞辅助的基本要素，其维持有效、高亲和力和持久的记忆应答。人激动性CD 40抗体已在动物肿瘤模型和黑素瘤患者中显示出具有显著的抗肿瘤活性，并且已在小鼠中显示出与TLR激动剂，尤其是TLR 3激动剂聚IC：LC组合的有效抗肿瘤作用。用鼠PBMC进行的实验表明，具有TLR 3激动剂的CD 40抗体增加了抗原特异性T细胞的产生，所述T细胞是溶解性的、功能性的、分泌γ-干扰素的效应细胞。当在动物模型中将CD 40激动性抗体与TLR 3激动剂聚IC：LC体内组合时，存在累加或甚至协同抗肿瘤作用。基于那些临床前数据和CD-40抗体的抗肿瘤活性的初步临床证据，我们提出在切除的高风险III/ IV期黑素瘤患者中进行一项试验性剂量递增试验，即在每组10名患者的队列中使用多肽疫苗和聚IC：LC与安慰剂或至少两种不同剂量的抗CD 40激动性抗体。终点将是毒性、MTD的定义和通过不同功能性T细胞测定测量的队列之间的免疫应答的比较。正在测试的假设是，当与TLR 3激动剂和黑素瘤疫苗组合时，CD 40激动性抗体导致抗原特异性的高度亲合力、长寿命记忆效应T细胞的产生的剂量依赖性增强。公共卫生相关性：在这项建议将支持的临床试验中，切除的III期和IV期黑色素瘤患者将有机会接受一种治疗方案，在我们看来，这种治疗方案有很大的机会使他们受益。这项试验的进行将提供重要的信息，可能有助于切除的黑色素瘤患者，这些患者因黑色素瘤死亡的风险非常高（80%或更高），并提供一个框架来测试新的和有前途的疫苗，这些疫苗可能使其他癌症患者受益。如果我们能够理解癌症患者产生具有高亲和力、持久抗肿瘤效应细胞的T细胞免疫的机制，那么所有美国人的总体健康状况都会得到改善。

DESCRIPTION (provided by applicant): Advances in our understanding of T cell activation at a molecular level have permitted the manipulation of T cell regulation in cancer patients. An important molecule involved in T cell regulation is CD40 which is expressed on antigen-presenting cells and B cells. The CD40-CD40 ligand interaction is an essential element in the generation of T cell help which maintains potent, high-avidity and long lasting memory responses. A human agonistic CD40 antibody has been shown in animal tumor models and in melanoma patients to have significant anti-tumor activity and has shown potent anti-tumor effects in mice in combination with TLR agonists, especially TLR3 agonist poly IC:LC. Experiments with murine PBMC indicate that CD40 antibody with TLR3 agonist increases the generation of antigen specific T cells that are lytic, functional, gamma-interferon secreting effector cells. When CD40 agonistic antibody is combined with TLR3 agonist poly IC:LC in vivo in animal models there is an additive or even a synergistic anti- tumor effect. Based on those pre-clinical data, and preliminary clinical evidence of anti-tumor activity of CD-40 antibody, we propose to perform a pilot escalating dose trial in resected high- risk stages III/ IV melanoma patients of a multi-peptide vaccine and poly IC:LC with placebo or at least two different doses of anti-CD40 agonistic antibody in cohorts of 10 patients each. The endpoints will be toxicity, definition of an MTD and a comparison of immune responses between the cohorts as measured by different functional T cell assays. The hypothesis being tested is that a CD40 agonistic antibody when combined with a TLR3 agonist and a melanoma vaccine results in a dose-dependent augmentation in the generation of highly avid, long lived memory- effector T cells that are antigen specific. PUBLIC HEALTH RELEVANCE: In the clinical trial that this proposal will support, patients with resected stages III and IV melanoma will have the opportunity to be treated with a regimen that has, in our opinion, a significant chance of benefiting them. The conduct of this trial will provide important information that may help patients with resected melanoma that have a very high (80% or more) risk of death from melanoma, and provide a framework to test new and promising vaccines that might benefit other patients with cancer. The general health of all Americans would be improved if we could understand the mechanisms by which T cell immunity with high-avidity, long lasting anti-tumor effector cells were generated in cancer patients.