Chimeric T Cell for Therpay of Hodgkin Disease

用于治疗霍奇金病的嵌合 T 细胞

基本信息

批准号：
7525151
负责人：
Barbara Savoldo
金额：
$ 30.87万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7525151
关键词：
Adoptive Transfer Antibodies Antigen Receptors Antigen Targeting Antigens Applications Grants Biopsy CC chemokine receptor 4 CCL17 gene CD28 gene CD30 Antigens CXCL10 gene Cell Differentiation process Cell physiology Cells Clinical Clinical Data Clinical Research Clinical Trials Complement 3d Receptors Cytokine Receptors Cytotoxic T-Lymphocytes Diffuse Disease Disease remission EBV-Specific Cytotoxic T-Lymphocyte Effectiveness Effector Cell Elements Employee Strikes Engineering Environment Growth Growth Factor Hodgkin Disease Homing Human Herpesvirus 4 Immune Immunotherapy In Vitro Individual Injection of therapeutic agent Interleukin-15 Lead Localized Maintenance Malignant Neoplasms Modification Molecular Monoclonal Antibodies Patients Personal Satisfaction Production Protein Overexpression Proteins Public Health Purpose Refractory Relapse SCID Mice Site Specificity T-Cell Receptor T-Lymphocyte TNFRSF8 gene Testing Toxic effect Transgenic Organisms Translating Tumor Antigens Ursidae Family Variant Viral Viral Antigens Viral Proteins Xenograft Model antibody conjugate autocrine base cancer cell cancer therapy cell motility chemokine chemokine receptor cytokine cytotoxic experience improved in vivo migration mouse model neoplastic cell paracrine pre-clinical preclinical study prevent receptor response success suicide gene tumor validation studies vector

项目摘要

DESCRIPTION (provided by applicant): Cytotoxic T-lymphocyte (CTL) therapy directed to Epstein-Barr virus (EBV) antigens has produced complete tumor responses in patients with EBV associated Hodgkin disease (HD) without toxicity. Many HD tumors, however, are EBV antigen negative. To extend immunotherapy to patients with such EBV negative HD, we propose to target the CD30 molecule, which is expressed by all malignant cells in both EBV positive and EBV negative HD. We hypothesize that we can exploit and extend the demonstrated effectiveness of EBV CTLs by redirecting them to the CD30 molecule, by forcing expression of a chimeric antigen receptor (CAR) targeting this molecule. We also hypothesize that we will be able to further engineer the CAR+ CTLs to overcome the molecular and cellular barriers that protect HD cells from immune attack. These hypotheses will be tested in three specific aims. In Aim 1, we propose to improve the homing of CAR+ CTLs to HD tumor cells by overexpressing the receptor (CCR4) for the chemokine TARC, which is constitutively produced by HD tumors, and whose receptor is lacking on CTLs. In Aim 2 we will evaluate whether expansion and persistence of our CCR4+ and CD30CAR+ CTLs is enhanced if these CTLs are further modified to produce their own growth cytokine (IL-15), which is essential to sustain their function. Finally, in Aim 3 we will analyze the interactions between regulatory T cells and our CAR+ CTLs. We will discover whether the modifications we have made allow the CAR+ CTLs to resist the inhibitory effects of the regulatory T cells that dominate sites of HD tumor, or whether alternative strategies will be required. The modifications we propose will be tested pre-clinically in vitro and in vivo and will form the basis of our continued clinical investigation of T- cell therapy for cancer. PUBLIC HEALTH RELEVANCE: We have had success in treating patients with relapsed Hodgkin disease (HD) by using their own immune cells directed to viral proteins that are often on the tumor cells. We now want to extend the application of this promising treatment by targeting other proteins that are on all HD cells, and by making the immune cells more potent.

描述（由申请人提供）：针对Epstein-Barr病毒（EBV）抗原的细胞毒性T淋巴细胞（CTL）疗法已在没有毒性的EBV相关HODGKIN疾病（HD）患者中产生了完全的肿瘤反应。但是，许多HD肿瘤为EBV抗原阴性。为了扩展对这种EBV阴性HD患者的免疫疗法，我们建议靶向CD30分子，CD30分子在EBV阳性和EBV阴性HD中均由所有恶性细胞表达。我们假设我们可以通过强迫针对该分子的嵌合抗原受体（CAR）的表达来利用和扩展EBV CTL通过将EBV CTL的有效性重定向到CD30分子。我们还假设我们将能够进一步设计CAR+ CTL，以克服保护HD细胞免疫攻击的分子和细胞屏障。这些假设将以三个特定目的进行检验。在AIM 1中，我们建议通过过度表达趋化因子TARC的受体（CCR4）来改善CAR+ CTL的归位为HD肿瘤细胞，趋化因子TARC是由HD肿瘤组成性产生的，其受体缺乏CTLS。在AIM 2中，我们将评估如果对这些CTL进行进一步修改以产生自己的生长细胞因子（IL-15），则可以增强CCR4+和CD30CAR+ CTL的扩展和持久性，这对于维持其功能至关重要。最后，在AIM 3中，我们将分析调节性T细胞与我们的CAR+ CTL之间的相互作用。我们将发现我们进行的修改是否允许CAR+ CTL抵抗主导HD肿瘤部位的调节T细胞的抑制作用，或者是否需要替代策略。我们提出的修改将在体外和体内进行前链链链术测试，并将构成我们对癌症T细胞治疗的临床研究的基础。公共卫生相关性：我们通过使用经常针对通常在肿瘤细胞上的病毒蛋白的免疫细胞来治疗复发性霍奇金疾病（HD）的患者。现在，我们希望通过靶向所有HD细胞上的其他蛋白质，并使免疫细胞更有效，以扩展这种有前途的治疗方法。