To Understand/Augment OX40-mediated Tumor Immunotherapy

描述(申请人提供)：可在荷瘤宿主中识别出癌症反应性免疫；然而，免疫“危险”信号的缺乏以及肿瘤微环境中免疫抑制因子/细胞的存在似乎扭转了平衡，有利于肿瘤的进展。我们和其他人最近发现，加入免疫激活抗体(如抗OX40、-CD40、-4-1BB和-CTLA-4)可以同时刺激获得性免疫和天然免疫，从而使平衡向有利于肿瘤免疫的方向倾斜，并导致肿瘤消退。特别是，我们的团队专注于靶向OX40蛋白的药物在荷瘤宿主中的免疫刺激特性，这些药物已在几个临床前小鼠癌症模型中显示出治疗前景。这项应用侧重于用OX40激动剂治疗荷瘤小鼠后，从肿瘤微环境(TME)中分离出来的T细胞和巨噬细胞内发生的变化。我们假设，在给予OX40激动剂后，TME内发生了免疫特异性变化，这些变化减少了导致T细胞介导的肿瘤细胞破坏的局部免疫抑制。其具体目的如下：1)检测OX40激动剂治疗后肿瘤微环境中肿瘤反应性CD8 T细胞数量和质量的变化，2)了解肿瘤相关巨噬细胞(TAM)在TME免疫抑制中的作用以及OX40治疗如何缓解这种抑制，3)测试在OX40刺激下重塑细胞因子环境是否可以在肿瘤内创造一个免疫允许的环境。最近，OX40特异性免疫系统的增强作用有所增加，因为我们已经生产出临床级别的抗OX40抗体，并作为第一个OX40特异性临床试验(I期研究)的一部分治疗了20名患者。了解OX40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OX40治疗与其他治疗方式相结合的临床试验的基础。 与公共卫生相关：众所周知，肿瘤会导致局部免疫抑制，最终使癌症不受免疫攻击的阻碍而生长。我们发现，一种免疫刺激抗体，抗OX40，交付给荷瘤宿主，增加了癌症特异性免疫，带来了积极的治疗益处。这个项目将剖析抗OX40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来改进未来的治疗。

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.