Enhancing Cancer Immunotherapy: Targeting the Tumor and Targeting the Host

项目总结/摘要 我们可以通过一秒钟刺激自然杀伤（NK）细胞的作用来增强抗体治疗 抗体的我们可以通过“原位接种”，即注射TLR， 配体直接进入一个肿瘤部位。我们正在对这两种方法进行临床试验， 结果非常有希望。加入阻断免疫检查点的抗体使得这些方法 更加强大我们将基于这些平台开展临床前和临床项目。 1.用刺激活化的NK细胞的第二抗体增强癌症的抗体治疗。我们 发现利妥昔单抗和其他单抗（曲妥珠单抗和西妥昔单抗）的治疗活性是 通过依次加入抗CD 137（41 BB）的第二抗体， NK杀伤细胞我们现在正在进行临床试验，测试在利妥昔单抗中加入CD 137抗体， B细胞淋巴瘤患者。与此同时，我们正在测试能与肿瘤结合的双特异性抗体， 以及NK细胞上的活化标记物。 2.治疗性原位疫苗接种。我们证明了一个全面的治疗性抗肿瘤免疫应答 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期临床试验 在淋巴瘤患者中进行的一项试验，测试了低剂量XRT联合肿瘤内注射， TLR激动剂和低剂量抗CTLA 4抗体。我们现在有临床前证据表明， 原位疫苗接种和伊替尼，一种BTK和ITK的抑制剂，一种在实体瘤中也起作用的组合。 3. B细胞淋巴瘤对免疫球蛋白（IG）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，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点，因为它们在肿瘤细胞中的所有恶性细胞上表达。 病人我们发现，患者的T细胞可以识别来自独特型的肽， 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.免疫监测的新方法 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中的细胞 微环境我们将从相同的肿瘤部位获得样本：在治疗前、治疗期间和治疗后。 实验性疗法，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活化的T细胞，以跟踪 真实的时间免疫治疗。我们将检测组织切片中的肿瘤反应细胞群， 多路离子束成像（MIBI）。该系统可以询问每个单元10个或更多个参数， 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.