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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：
8088047
负责人：
Barbara Savoldo
金额：
$ 30.9万
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/8088047
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 Therapy Cell physiology Cells Clinical Clinical Data Clinical Research Clinical Trials 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 Health Hodgkin Disease Homing Human Herpesvirus 4 Immune Immunotherapy In Vitro Individual Injection of therapeutic agent Interleukin-15 Lead Maintenance Malignant Neoplasms Modification Molecular Monoclonal Antibodies Patients Production Proteins Refractory Regulatory T-Lymphocyte Relapse SCID Mice Site Specificity T cell differentiation T-Cell Receptor T-Lymphocyte TNFRSF8 gene Testing Toxic effect Transgenic Organisms Translating Tumor Antigens Ursidae Family Variant Viral Antigens Viral Proteins Xenograft Model antibody conjugate autocrine base cancer cell cell motility chemokine chemokine receptor cytokine cytotoxic effective therapy experience improved in vivo migration mouse model neoplastic cell overexpression 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 EBV 相关霍奇金病（HD）患者中产生了完全的肿瘤反应，且无毒性。然而，许多 HD 肿瘤的 EBV 抗原呈阴性。为了将免疫治疗扩展到此类 EBV 阴性 HD 患者，我们建议靶向 CD30 分子，该分子在 EBV 阳性和 EBV 阴性 HD 中的所有恶性细胞中表达。我们假设我们可以通过将 EBV CTL 重定向到 CD30 分子，通过强制表达针对该分子的嵌合抗原受体 (CAR)，来利用和扩展 EBV CTL 已证明的有效性。我们还假设我们将能够进一步设计 CAR+ CTL，以克服保护 HD 细胞免受免疫攻击的分子和细胞屏障。这些假设将在三个具体目标中得到检验。在目标 1 中，我们建议通过过表达趋化因子 TARC 的受体 (CCR4) 来改善 CAR+ CTL 向 HD 肿瘤细胞的归巢，TARC 是由 HD 肿瘤组成型产生的，而 CTL 上缺乏该受体。在目标 2 中，我们将评估如果 CCR4+ 和 CD30CAR+ CTL 被进一步修饰以产生其自身的生长细胞因子 (IL-15)（这对于维持其功能至关重要），这些 CTL 的扩增和持久性是否会得到增强。最后，在目标 3 中，我们将分析调节性 T 细胞和 CAR+ CTL 之间的相互作用。我们将发现我们所做的修改是否允许 CAR+ CTL 抵抗主导 HD 肿瘤部位的调节性 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临床前体外和体内进行测试，并将构成我们对癌症 T 细胞疗法持续临床研究的基础。公共健康相关性：我们通过使用针对肿瘤细胞上常见病毒蛋白的自身免疫细胞，成功治疗了复发性霍奇金病 (HD) 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，来扩展这种有希望的治疗方法的应用。