Enhancing Cancer Immunotherapy: Targeting the Tumor and Targeting the Host

增强癌症免疫治疗：针对肿瘤和针对宿主

• 批准号: 10229582
• 负责人: RONALD LEVY
• 金额: $ 84.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-02 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229582
• 关键词: Activated Natural Killer Cell; Agonist; Antibodies; Antibody Therapy; B-Cell Lymphomas; B-Lymphocytes; Binding; Bispecific Antibodies; Blocking Antibodies; Cells; Cetuximab; Clinical; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; Data Set; Dose; Flow Cytometry; Histocompatibility Antigens Class II; Imaging Techniques; Immune; Immune Targeting; Immune response; Immune system; Immunoglobulin Idiotypes; Immunoglobulins; Immunologic Monitoring; Immunotherapeutic agent; Immunotherapy; Injections; Investigational Therapies; Killer Cells; Ligands; Lymphoma; Malignant Neoplasms; Methods; Modality; Monitor; Monoclonal Antibodies; Multiplexed Ion Beam Imaging; Natural Killer Cells; Patients; Peptides; Phase I/II Clinical Trial; Population; Public Health; Resolution; Sampling; Site; Solid Neoplasm; System; T-Lymphocyte; Testing; Therapeutic; Time; Tissue Embedding; Tissues; Work; anti-CTLA4 antibodies; anti-tumor immune response; base; cancer cell; cancer immunotherapy; cancer therapy; design; high dimensionality; immune checkpoint; in situ vaccination; inhibitor/antagonist; neoplastic cell; non-invasive imaging; novel; pre-clinical; rituximab; synergism; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT We can enhance antibody therapy by stimulating the action of natural killer (NK) cells by a single second antibody. We can trigger a global therapeutic immune response by “in situ vaccination”, the injection of TLR ligands directly into one tumor site. We are conducting clinical trials of both of these approaches and the early results are very promising. The addition of antibodies that block immune checkpoints make these approaches even more powerful. We will conduct preclinical and clinical projects based on these platforms. 1. Enhancing antibody therapy of cancer with a second antibody that stimulates activated NK cells. We discovered that the therapeutic activity of Rituximab and other mAbs (Traztuzumab and Cetuximab) are enhanced by the sequential addition of a second antibody against CD137 (41BB), an activation molecule on the NK killer cells. We are now leading clinical trials that test the addition of CD137 antibodies to Rituximab in patients with B cell lymphoma. Simultaneously, we are testing bispecific antibodies that bind both to the tumor and to activation markers on NK cells. 2. Therapeutic In Situ Vaccination. We demonstrated that a global therapeutic anti-tumor immune response can be triggered by the injection of TLR ligands into a single tumor site. We are conducting a phase I/II clinical trial in lymphoma patients, testing the combination of low dose XRT followed by intra-tumoral injection of both a TLR agonist and a low dose of anti CTLA4 antibody. We now have preclinical evidence for synergy between in situ vaccination and Ibrutinib, an inhibitor of BTK and ITK, a combination that works also in solid tumors. 3. The Immune Response against immunoglobulin (Ig)-derived peptides in B cell lymphoma B-cell lymphomas express a unique immunoglobulin idiotype that distinguishes malignant cells from normal B- cells. Idiotypes are ideal targets for immunotherapy because they are expressed on all the malignant cells in the patient. We discovered that patients have T cells that recognize peptides derived from idiotypes that are displayed in MHC class II molecules. Now we will design new immunotherapy directed at MHC II-idiotypes. 4. New Methods of Immune Monitoring A critical component of each of our immunotherapy projects is an intense focus on monitoring cells in the tumor microenvironment. We will obtain samples from the same tumor sites: before, during, and after the experimental therapies and analyze the cell populations by high-dimensional flow cytometry. These data sets will be compared across trials that test different modalities of immunotherapy. We will detect activated T cells in patients by novel non-invasive imaging techniques to track the effects of immunotherapies in real time .We will detect the tumor-reactive cell populations in tissue sections by Multiplexed Ion Beam Imaging (MIBI). This system can interrogate 10 or more parameters per cell with high spatial resolution on sections from FFPE embedded tissues.

项目概要/摘要 我们可以通过一秒刺激自然杀伤 (NK) 细胞的作用来增强抗体治疗 抗体。我们可以通过“原位疫苗接种”（注射 TLR）引发全球治疗性免疫反应 配体直接进入一个肿瘤部位。我们正在对这两种方法和早期的方法进行临床试验 结果非常有希望。添加阻断免疫检查点的抗体使这些方法 甚至更强大。我们将基于这些平台开展临床前和临床项目。 1. 使用刺激活化 NK 细胞的二抗来增强癌症的抗体治疗。我们 发现利妥昔单抗和其他单克隆抗体（曲妥珠单抗和西妥昔单抗）的治疗活性 通过连续添加抗 CD137 (41BB) 的第二抗体来增强，CD137 是一种激活分子 NK 杀伤细胞。我们现在正在领导临床试验，测试在利妥昔单抗中添加 CD137 抗体 B细胞淋巴瘤患者。同时，我们正在测试与肿瘤结合的双特异性抗体 以及 NK 细胞上的激活标记。 2. 治疗性原位疫苗接种。我们证明了全球治疗性抗肿瘤免疫反应 可以通过将 TLR 配体注射到单个肿瘤部位来触发。我们正在进行I/II期临床 在淋巴瘤患者中进行的试验，测试了低剂量 XRT 和肿瘤内注射两种药物的组合 TLR 激动剂和低剂量的抗 CTLA4 抗体。我们现在有临床前证据证明两者之间的协同作用 原位疫苗接种和依鲁替尼（BTK 和 ITK 抑制剂）的组合也适用于实体瘤。 3. B 细胞淋巴瘤中针对免疫球蛋白 (Ig) 衍生肽的免疫反应 B 细胞淋巴瘤表达独特的免疫球蛋白独特型，可将恶性细胞与正常 B 细胞区分开来。 细胞。独特型是免疫治疗的理想靶标，因为它们在所有恶性细胞上表达 病人。我们发现患者的 T 细胞能够识别源自独特型的肽，这些肽是 显示在 MHC II 类分子中。现在我们将设计针对 MHC II 独特型的新免疫疗法。 4. 免疫监测新方法 我们每个免疫治疗项目的一个关键组成部分是密切关注肿瘤细胞的监测 微环境。我们将从相同的肿瘤部位获取样本：治疗前、治疗期间和治疗后 实验疗法并通过高维流式细胞术分析细胞群。 这些数据集将在测试不同免疫治疗方式的试验中进行比较。 我们将通过新型非侵入性成像技术检测患者体内活化的 T 细胞，以跟踪 实时免疫治疗。我们将通过以下方式检测组织切片中的肿瘤反应细胞群 多重离子束成像 (MIBI)。该系统可以以高速度询问每个细胞 10 个或更多参数 FFPE 包埋组织切片的空间分辨率。