Improving T-cell therapies for neuroblastoma

改善神经母细胞瘤的 T 细胞疗法

基本信息

批准号：
8056476
负责人：
Gianpietro Dotti
金额：
$ 44.76万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-05 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8056476
关键词：
Adoptive Cell Transfers Adoptive Transfer Affect Aliquot Animals Antigen Receptors Antigen-Presenting Cells Antigens Biological Assay Blood Circulation CD3 Antigens CD8-Positive T-Lymphocytes Cell Line Cell Therapy Cells Cellular Immunity Child Chimeric Proteins Clinical Clinical Trials Complex Cytokine Receptors Cytotoxic T-Lymphocytes Data Disease Disease remission Dose EBV-Specific Cytotoxic T-Lymphocyte Engineering Epitopes Figs - dietary Gene Transfer Growth Human Herpesvirus 4 Immune Immune response Immunotherapy In Vitro Infusion procedures Interleukin 7 Receptor Interleukin-15 Interleukin-2 Interleukin-7 Lymphoid Malignant - descriptor Measures Memory Monitor Monoclonal Antibodies Necrosis Neuroblastoma Outcome Patients Pediatric Neoplasm Phase Phase I Clinical Trials Pre-Clinical Model Production Radiation Recombinant Interleukins Recombinants Recurrent disease Refractory Regulatory T-Lymphocyte Relapse Resistance Retroviridae Safety Signal Transduction Specificity Study Subject T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Therapeutic Toxic effect Transgenic Organisms Xenograft Model antigen binding arm base chemotherapy cytokine cytotoxic high risk human subject improved in vivo neoplastic cell neuroblast peripheral blood public health relevance receptor reconstitution response success treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): The intent of this project is to improve the therapeutic potential of T-cell therapy targeting neuroblastoma (NB) by co-expressing a tumor-specific chimeric antigen receptor (CAR) and a cytokine receptor. NB is the most common malignant extracranial tumor of childhood, and children with high-risk disease continue to have a poor outcome despite intensive therapy. New treatment strategies are therefore required. We have recently demonstrated that adoptive transfer of Epstein-Barr-virus-specific CTLs (EBV-CTLs), genetically modified to express a chimeric antigen receptor (CAR) targeting GD2 expressed by neuroblasts, persisted in the circulation for 6 weeks and determined objective tumor responses in 4/8 patients with refractory/relapsed NB. Since it is now evident that tumor responses to CTL infusions correlate with the persistence/expansion of these CTLs, we propose a new strategy to improve the growth of adoptively transferred CAR-GD2-EBV-CTLs. Although in vivo expansion of CTLs can be accomplished in the acutely lymphodepleted host, profund lymphodepletion may be excessively toxic to the majority of refractory/resistant NB patients who have already received significant doses of chemotherapy and radiation. Moreover, the administration of high-doses of IL-2 significantly contributes in increasing the toxicity and in favoring the expansion of regulatory T cells (Tregs) that inhibit the function of anti-tumor CTLs. In contrast to IL-2, the administration of recombinant IL-7 (rIL-7) seems well tolerated and produces polyclonal expansion of naive CD4+ and CD8+ T lymphocytes, without evident increase of Tregs, suggesting that this cytokine can be used to improve the persistence/expansion of adoptively transferred CTLs. Unfortunately, IL-7 has only limited activity on ex vivo expanded tumor-directed CTLs because the expression of IL-7 receptor alpha (IL-7Ra) is rapidly down-regulated once T cells are exposed to antigen stimulation. We found that gene transfer can be used to restore functional IL-7Ra in EBV- CTLs without affecting their antigen specificity and effector function. Based on these data, we propose to evaluate in a preclinical model and then in a phase I clinical trial whether EBV-CTLs co-expressing CAR-GD2 and IL-7Ra infused into refractory/relapsed NB patients safely expand and persist in response to the administration of rIL-7, and whether such engineered CTLs have anti-tumor activity. PUBLIC HEALTH RELEVANCE: We have had success in treating patients with neuroblastoma by using their own immune cells modified with a chimeric molecule that eliminate the tumor cells. In this project we intend to arm these cells to be more potent by improving their growth when infused into the patients with neuroblastoma.

描述（由申请人提供）：该项目的目的是通过共表达肿瘤特异性嵌合抗原受体（CAR）和细胞因子受体来提高针对神经母细胞瘤（NB）的T细胞疗法的治疗潜力。 NB 是儿童最常见的恶性颅外肿瘤，患有高危疾病的儿童尽管经过强化治疗，结果仍然不佳。因此需要新的治疗策略。我们最近证明，通过基因改造表达针对神经母细胞表达的 GD2 的嵌合抗原受体 (CAR) 的 Epstein-Barr 病毒特异性 CTL (EBV-CTL) 的过继转移，可在循环中持续 6 周，并确定目标肿瘤4/8 的难治性/复发性 NB 患者有反应。由于现在很明显，肿瘤对 CTL 输注的反应与这些 CTL 的持久性/扩展相关，因此我们提出了一种新策略来改善过继转移的 CAR-GD2-EBV-CTL 的生长。虽然 CTL 的体内扩增可以在急性淋巴细胞清除宿主中完成，但深度淋巴细胞清除可能对大多数已经接受过大剂量化疗和放疗的难治性/耐药性 NB 患者具有过度毒性。此外，高剂量IL-2的施用显着增加了毒性并有利于抑制抗肿瘤CTL功能的调节性T细胞（Treg）的扩增。与 IL-2 相比，重组 IL-7 (rIL-7) 的施用似乎具有良好的耐受性，并产生初始 CD4+ 和 CD8+ T 淋巴细胞的多克隆扩增，而没有明显增加 Tregs，这表明该细胞因子可用于改善过继转移的 CTL 的持续/扩展。不幸的是，IL-7 对离体扩增的肿瘤定向 CTL 的活性有限，因为一旦 T 细胞受到抗原刺激，IL-7 受体 α (IL-7Ra) 的表达就会迅速下调。我们发现基因转移可用于恢复 EBV-CTL 中的功能性 IL-7Ra，而不影响其抗原特异性和效应子功能。基于这些数据，我们建议在临床前模型中进行评估，然后在 I 期临床试验中评估共表达 CAR-GD2 和 IL-7Ra 的 EBV-CTL 输注到难治性/复发性 NB 患者体内是否能够安全扩展并持续存在，以响应rIL-7 的施用，以及此类工程 CTL 是否具有抗肿瘤活性。公共健康相关性：我们已经成功地使用经过嵌合分子修饰的自身免疫细胞来治疗神经母细胞瘤患者，从而消除肿瘤细胞。在这个项目中，我们打算通过将这些细胞注入神经母细胞瘤患者体内时改善它们的生长来增强它们的效力。