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: 9755369
• 负责人: RONALD LEVY
• 金额: $ 85.3万
• 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/9755369
• 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; Immunotherapy; In Situ; Injections; Investigational Therapies; Killer Cells; Ligands; Lymphoma; Malignant Neoplasms; Methods; Modality; Monitor; Monoclonal Antibodies; Multiplexed Ion Beam Imaging; Natural Killer Cells; Patients; Peptides; Phase; Population; Public Health; Resolution; Sampling; Site; Solid Neoplasm; System; T-Lymphocyte; Testing; Therapeutic; Time; Tissue Embedding; Tissues; Vaccination; Work; anti-CTLA4; anti-tumor immune response; base; cancer cell; cancer immunotherapy; cancer therapy; design; high dimensionality; immune checkpoint; 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.

项目摘要/摘要 我们可以通过刺激自然杀手（NK）细胞的作用来增强抗体疗法 抗体。我们可以通过“原位疫苗接种”（注射TLR）触发全局的热免疫反应 配体直接进入一个肿瘤部位。我们正在进行这两种方法和早期的临床试验 结果非常有前途。添加阻断免疫检查点的抗体使这些方法 更强大。我们将根据这些平台进行临床前和临床项目。 1。用第二种抗体刺激活化的NK细胞增强癌症的抗体疗法。我们 发现利妥昔单抗和其他mab的治疗活性（traztuzumab和cetuximab）是 通过对CD137（41Bb）的第二抗体的顺序添加，这是一种激活分子 NK杀手细胞。现在，我们正在领导临床试验，该试验测试了在利妥昔单抗中添加CD137抗体 B细胞淋巴瘤患者。同时，我们正在测试两者与肿瘤结合的双特异性抗体 并在NK细胞上激活标记。 2。原位疫苗接种。我们证明了全球疗法抗肿瘤免疫反应 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 在淋巴瘤患者中试验，测试低剂量XRT的组合，然后肿瘤内注射两种 TLR激动剂和低剂量的抗CTLA4抗体。现在，我们有临床前证明在 BTK和ITK的抑制剂IBATION疫苗接种和Ibrutinib，这是一种在实体瘤中起作用的组合。 3。针对B细胞淋巴瘤中免疫球蛋白（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特性，将恶性细胞与正常B-区分开 细胞。白痴是免疫疗法的理想靶标，因为它们在所有恶性细胞中表达 病人。我们发现患者的T细胞识别出源自白痴的肽的T细胞 显示在MHC II类分子中。现在，我们将设计针对MHC II-IDiotypes的新免疫疗法。 4。免疫监测的新方法 我们每个免疫疗法项目的一个关键组成部分是强烈地关注监测肿瘤中的细胞 微环境。我们将从相同的肿瘤部位获得样品： 实验疗法并通过高维流式细胞仪分析细胞群。 这些数据集将在测试免疫疗法不同方式的试验中进行比较。 我们将通过新颖的非侵入性成像技术检测患者中的T细胞，以跟踪 实时免疫疗法。我们将通过 多路复用离子束成像（MIBI）。该系统可以用高的每个单元格询问10个或更多参数 来自FFPE嵌入组织的切片的空间分辨率。