To Understand/Augment OX40-mediated Tumor Immunotherapy

描述（由申请人提供）：可以在荷瘤宿主中鉴定出癌症反应性免疫;然而，免疫学“危险”信号的缺乏以及肿瘤微环境中免疫抑制因子/细胞的存在似乎使平衡倾向于肿瘤进展。我们和其他人最近发现，添加刺激适应性免疫和先天性免疫的免疫活化Ab（例如抗-OX 40、-CD 40、-4 - 1BB和-CTLA-4）可以使平衡偏向肿瘤免疫并导致肿瘤消退。特别是，我们的团队专注于靶向肿瘤宿主中OX 40蛋白的药物的免疫刺激特性，这些药物在几种临床前小鼠癌症模型中显示出治疗前景。本申请集中于用0X 40激动剂治疗荷瘤小鼠后发生的从肿瘤微环境（TME）分离的T细胞和巨噬细胞内的变化。我们假设，免疫特异性变化发生在TME后，OX 40激动剂管理，减少局部免疫抑制，导致T细胞介导的肿瘤细胞的破坏。具体目标如下：1）检查0X 40激动剂治疗后肿瘤微环境内肿瘤反应性CD 8 T细胞的定量和定性变化，2）了解肿瘤相关巨噬细胞（TAM）在TME免疫抑制中的作用以及OX 40治疗如何消除这种抑制，以及3）为了测试在OX 40刺激的背景下重塑细胞因子环境是否可以在肿瘤内创建免疫容许环境。免疫系统的OX 40特异性增强最近增加了相关性，因为我们已经产生了临床级抗OX 40，并作为第一个OX 40特异性临床试验（I期研究）的一部分治疗了20名患者。了解OX 40治疗后TME内发生的变化可能最终发现新的途径和新的机制，这可能是未来将联合收割机OX 40治疗与其他治疗方式相结合的临床试验的基础。 公共卫生相关性：众所周知，肿瘤会诱导局部免疫抑制，最终使癌症不受免疫攻击的阻碍。我们已经发现，免疫刺激抗体，抗OX 40，交付给荷瘤宿主增加癌症特异性免疫，导致积极的治疗效益。该项目将剖析抗OX 40治疗后肿瘤微环境中发生的免疫特异性变化，我们将利用这些信息使未来的治疗更好。

DESCRIPTION (provided by applicant): Cancer-reactive immunity can be identified in tumor-bearing hosts; however, the paucity of immunologic "danger" signals as well as the presence of immunosuppressive factors/cells within the tumor microenvironment appears to tip the balance in favor of tumor progression. We and others have recently found that the addition of immune activating Ab(s) (e.g. anti-OX40, -CD40, -4-1BB, and -CTLA-4) that stimulate both adaptive and innate immunity can tip the balance in favor of tumor immunity and lead to tumor regression. In particular, our group has focused on the immune stimulating properties of agents targeting the OX40 protein in tumor-bearing hosts, which have shown therapeutic promise in several preclinical mouse cancer models. This application focuses on the changes within T cells and macrophages isolated from the tumor microenvironment (TME) that occur following treatment of tumor-bearing mice with OX40 agonists. We hypothesize that immune-specific changes occur within the TME after OX40 agonist administration that reduce local immune suppression leading to T cell-mediated destruction of tumor cells. The specific aims are as follows; 1) To examine the quantitative and qualitative changes in tumor-reactive CD8 T cells within the tumor microenvironment after OX40 agonist treatment, 2) To understand the role that tumor-associated macrophages (TAMs) play in immune suppression of the TME and how OX40 therapy alleviates this suppression and 3) To test whether reshaping the cytokine milieu in the context of OX40 stimulation can create an immune permissive environment within the tumor. OX40-specific augmentation of the immune system has recently increased in relevance, because we have produced clinical grade anti-OX40 and have treated 20 patients as part the first OX40-specific clinical trial (phase I study). Understanding the changes that occur within the TME following OX40 treatment may ultimately discover new pathways and novel mechanisms, which could be the basis for future clinical trials that combine OX40 therapy with other treatment modalities. PUBLIC HEALTH RELEVANCE: Tumors are known to induce local immune suppression, which ultimately allows the cancer to grow unhindered by immune attack. We have found that an immune-stimulating antibody, anti-OX40, delivered to tumor-bearing hosts increases cancer-specific immunity leading positive therapeutic benefit. This project will dissect the immune-specific changes that occur within the tumor microenvironment following anti-OX40 treatment and we will use this information to make the therapy better in the future.