Enhancing Cancer Immunotherapy: Targeting the Tumor and Targeting the Host

项目摘要/摘要 我们可以通过刺激自然杀伤(NK)细胞的活动一秒钟来加强抗体治疗 抗体。我们可以通过“原位接种”、注射TLR来触发全球治疗性免疫反应。 将配体直接连接到一个肿瘤部位。我们正在对这两种方法和早期的 结果是非常有希望的。添加阻断免疫检查点的抗体使这些方法 甚至更强大。我们将在这些平台的基础上开展临床前和临床项目。 1.用第二种抗体刺激活化的NK细胞，以加强癌症的抗体治疗。我们 发现利妥昔单抗和其他单抗(曲祖单抗和西妥昔单抗)的治疗活性是 通过连续添加第二个针对CD137(41BB)的抗体来增强作用，CD137(41BB)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。 NK细胞表面的活化标志物。 2.治疗性原位接种。我们证明了一种全球治疗性抗肿瘤免疫反应 可通过将TLR配体注射到单个肿瘤部位而触发。我们正在进行I/II期临床试验 在淋巴瘤患者中的试验，测试低剂量XRT和肿瘤内注射的组合 TLR激动剂和小剂量抗CTLA4抗体。我们现在有了临床前证据表明 原位疫苗和伊布鲁替尼，一种BTK和ITK的抑制剂，这两种药物的组合也适用于实体肿瘤。 3.B细胞淋巴瘤对免疫球蛋白衍生肽的免疫应答 B细胞淋巴瘤表达一种独特的免疫球蛋白独特型，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点，因为它们表达在所有的恶性肿瘤细胞上 病人。我们发现，患者有识别来自独特型的多肽的T细胞 显示在MHC II类分子中。现在，我们将针对MHC II-独特型设计新的免疫疗法。 4.免疫监测的新方法 我们每个免疫治疗项目的一个关键组成部分是对肿瘤细胞的密切关注 微环境。我们将从相同的肿瘤部位获取样本：治疗前、治疗中和治疗后 实验治疗，并用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疗法模式的试验中进行比较。 我们将通过新的非侵入性成像技术检测患者体内激活的T细胞，以跟踪 实时免疫治疗。我们将通过以下方法检测组织切片中的肿瘤反应细胞群 多路传输离子束成像(MIBI)。该系统可以在每个单元中查询10个或更多的参数，具有高的 FFPE包埋组织切片的空间分辨率。

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.