CD40 and TLR Agonists in Melanoma

描述（由申请人提供）：我们在分子水平上对T细胞活化的理解取得了进展，这使得在癌症患者中操纵T细胞调节成为可能。参与T细胞调控的一个重要分子是CD40，它在抗原呈递细胞和B细胞上表达。CD40-CD40配体相互作用是T细胞帮助产生的重要因素，T细胞帮助维持有效、高活性和持久的记忆反应。在动物肿瘤模型和黑色素瘤患者中，一种人类激动性CD40抗体已被证明具有显著的抗肿瘤活性，并且在小鼠中与TLR激动剂，特别是TLR3激动剂poly IC:LC联合使用时显示出强大的抗肿瘤作用。小鼠PBMC实验表明，CD40抗体与TLR3激动剂可增加抗原特异性T细胞的产生，这些细胞是具有裂解功能的γ -干扰素分泌效应细胞。在动物体内模型中，CD40激动抗体与TLR3激动剂poly IC:LC联用时，具有相加甚至协同的抗肿瘤作用。基于这些临床前数据和CD-40抗体抗肿瘤活性的初步临床证据，我们建议在切除的高风险III/ IV期黑色素瘤患者中进行一项先导剂量递增试验，多肽疫苗和poly IC:LC联合安慰剂或至少两种不同剂量的抗cd40激动抗体，每组10例患者。终点将是毒性，MTD的定义以及通过不同功能T细胞测定测定的队列之间免疫反应的比较。正在测试的假设是，当CD40激动抗体与TLR3激动剂和黑色素瘤疫苗联合使用时，会导致高度活跃的、长寿命的、抗原特异性的记忆效应T细胞的产生呈剂量依赖性增加。公共卫生相关性：在该提案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方案的治疗，在我们看来，这种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，可能有助于切除黑色素瘤的患者，这些患者死于黑色素瘤的风险非常高（80%或更多），并提供一个框架来测试新的和有希望的疫苗，这些疫苗可能使其他癌症患者受益。如果我们能够了解在癌症患者体内产生具有高活性、持久抗肿瘤效应细胞的T细胞免疫的机制，所有美国人的总体健康状况将得到改善。

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.