Immune Therapy

免疫治疗

• 批准号: 8235336
• 负责人: Thomas J Kipps
• 金额: $ 25.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235336
• 关键词: ABL1 gene; Adenovirus 5-CD40-L Vector; Adult; Antibodies; Antigen Receptors; Apoptosis; Autoantibodies; Autologous; CCL3 gene; CCL4 gene; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Cytotoxic agent; Data; Development; Disease; Disease Progression; Drug resistance; Genes; Immunotherapy; In Vitro; Instruction; Intravenous infusion procedures; Liposomes; Lymphocyte Subset; Lymphoid Tissue; Mononuclear; Nurses; Pathogenesis; Patients; Pharmaceutical Preparations; Phosphotransferases; Play; RORA gene; Recombinants; Recruitment Activity; Refractory; Research; Role; Sampling; Serum; Simulate; Surrogate Markers; T-Lymphocyte; Time; Tissues; Vaccines; c-abl Proto-Oncogenes; cellular transduction; chemokine; chemotherapy; cytotoxic; effective therapy; immune activation; lenalidomide; leukemia; novel; precursor cell; pro-apoptotic protein; receptor; response; treatment strategy

PROJECT SUMMARY (See instructions): We examined the response of patients who received intravenous infusions of autologous leukemia cells transduced ex vivo to express a recombinant CDI 54 (termed "Ad-CD154 gene-Rx"). We found such treatment could induce p53-dependent genes encoding pro-apoptotic proteins in non-transduced "bystander" CLL cells that lacked functional p53 via c-abl-kinase activafion of TAp7S. Activation of TAp7S could sensitize such drug-resistant CLL cells to the cytotoxic effects of drugs that ordinarily require functional p53. Ad-CD154 gene Rx also could induce auto antibodies to ROR1, which found absent on normal adult tissues, but expressed on CLL cells of virtually all cases, where it plays an apparent role in pathogenesis. We hypothesize that treatment of CLL patients with lenalidomide might mimic these effects of Ad-CDI 54 gene Rx. We also propose that ROR1could serve as an excellent target for development of novel therapies. Finally, ROR1 is one of several receptors for factors engaged in the cross talk between CLL cells and its microenvironment. CLL cells simulated by nurse like cells (NLC) found in the CLL microenvironment are induced to elaborate chemokines (CCLS and CCL4) that can recruit T cells and NLC-precursor cells to the microenvironment. Preliminary data suggest that the serum levels of CCL3/CCL4 might serve as surrogate markers of disease activity and possibly of early response to novel therapies intended to induce immune activation or cause disruption of the CLL microenvironment that are being investigated by the CRC. To take advantage of these observations we have the following specific aims: 1. Evaluate whether lenalidomide can induce anti-ROR1 auto antibodies and mimic the capacity of Ad-CDI 54 Gene Rx to enhance sensitivity of drug-resistant CLL cells to chemotherapy. Determine whether such effects are noted primarily in patients who are most likely to respond favorably to lenalidomide; 2. Evaluate expression levels of CCLS and CCL4 in relation to disease progression or response to treatment strategies intended to induce immune activation or disrupt the CLL microenvironment; 3. Evaluate strategies to target RORI with RORI vaccines, anti-ROR1 mAbs, T cells bearing ROR1-specific chimeric antigen receptors, or drug-laden liposomes that target ROR1.

项目总结（见说明）： 我们检查了接受自体白血病细胞静脉输注的患者的反应， 体外转导以表达重组CD 154（称为“Ad-CD 154基因-Rx”）。我们发现这样的 处理可以通过TAp 7S的c-abl-激酶激活在缺乏功能性p53的非转导的“旁观者”CLL细胞中诱导编码促凋亡蛋白的p53依赖性基因。TAp 7S的激活可以使这种耐药CLL细胞对通常需要功能性p53的药物的细胞毒性作用敏感。Ad-CD 154基因Rx还可以诱导针对ROR 1的自身抗体，这种抗体在正常成人组织中不存在，但在几乎所有病例的CLL细胞上表达，在发病机制中发挥明显作用。我们假设，CLL患者来那度胺治疗可能模仿这些影响的Ad-CDI 54基因Rx。我们还建议ROR 1可以作为开发新疗法的一个很好的靶点。 最后，ROR 1是参与CLL细胞及其微环境之间串扰的因子的几种受体之一。由在CLL微环境中发现的护士样细胞（NLC）模拟的CLL细胞被诱导为精心制作的趋化因子（CCLS和CCL 4），其可以将T细胞和NLC前体细胞募集到微环境中。初步数据表明，血清CCL 3/CCL 4水平可能作为疾病活动的替代标志物，并可能作为对CRC正在研究的旨在诱导免疫激活或导致CLL微环境破坏的新疗法的早期反应。为了利用这些观察结果，我们有以下具体目标：1。评价来那度胺是否能诱导抗ROR 1自身抗体，并模拟Ad-CDI 54 Gene Rx增强耐药CLL细胞对化疗敏感性的能力。确定这些影响是否主要发生在最有可能对来那度胺产生良好反应的患者中; 2.评估CCLS和CCL 4的表达水平与疾病进展或对旨在诱导免疫激活或破坏CLL微环境的治疗策略的反应; 3.评估使用RORI疫苗、抗ROR 1 mAb、携带ROR 1特异性嵌合抗原受体的T细胞或靶向ROR 1的载药脂质体靶向RORI的策略。