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Examining the impact of endogenous CD28 signaling on CAR T cells

检查内源性 CD28 信号传导对 CAR T 细胞的影响

基本信息

批准号：
10318192
负责人：
Scott Henry Olejniczak
金额：
$ 8.41万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-11 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318192
关键词：
Adoptive Immunotherapy Affect Antibody Activation Antigen-Presenting Cells Antigens Applications Grants Autoimmune Diseases B lymphoid malignancy B-Lymphocytes Biological Response Modifier Therapy CAR T cell therapy CD19 gene CD28 gene CD80 gene CD86 gene CTLA4 gene Cancer Patient Cell Death Cell Lineage Cell Maturation Cell physiology Cells Clinical Clinical Research Data Distal Epigenetic Process FDA approved Functional disorder Gene Expression Genes Genetic Goals Hematopoietic Neoplasms Immune In complete remission Knowledge Ligands Literature Malignant - descriptor Membrane Modeling Modification Multiple Myeloma Occupations Patients Persons Pharmaceutical Preparations Pharmacology Physiological Property Proteins Publishing Receptor Signaling Refractory Relapse Reporting Research Resistance Rheumatoid Arthritis Signal Transduction Surface Surface Antigens T cell response T-Cell Receptor T-Lymphocyte Testing Treatment Failure Up-Regulation blood treatment cancer cell cancer type cell killing cellular engineering cellular transduction chemotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical development clinical translation early phase clinical trial effector T cell exhaust exhaustion improved in vivo inhibitor manufacturing process mutant neoplastic cell novel strategies objective response rate phase II trial preclinical study programs receptor relapse patients response standard of care tumor

项目摘要

Project Abstract/Summary. Recent advances in immune cell engineering have revolutionized the treatment of blood cancers. Genetic modification of T cells, whose physiological job is to kill infected and mutant cells throughout our bodies, with Chimeric Antigen Receptors (CARs) can redirect T cell killing activity against malignant cells that express certain target proteins on their surface. CARs are built to mimic physiological T cell signaling, which is unique in its requirement for two signals provided by the T cell receptor (TCR) and co-receptors, such as CD28, to induce T cell function. Recent clinical studies in multiple myeloma (MM), a common incurable blood cancer, have shown that CAR T cells are remarkably effective at treating patients who do not respond to standard of care chemotherapies. Despite this, most MM patients relapsed within a year of CAR T cell therapy and the cause of their relapses was not readily apparent. The long-term goal of the project proposed in this grant application is to use our knowledge or T cell signaling to make CAR T cell therapy for MM more effective. To this end, we have found that endogenous CD28 on CAR T cells disrupts their ability to kill MM cells that express CD28 stimulatory proteins CD80 and CD86. However, the same endogenous CD28 is essential for making CAR T cells and we have also found that the CD28 signal provided during the CAR T cell manufacturing process helps determine how good of tumor killers CAR T cells become. Proposed studies seek to 1) identify ways to manipulate CD28 signaling during CAR T cell manufacture that can improve their long-term ability to kill MM cells in patients, and 2) determine how endogenous CD28 signaling causes dysfunction of CAR T cells. Results of these studies will have direct clinical implications because adjustments to the CAR T cell manufacturing process could be rapidly implemented and a drug that blocks CD28 activation, abatacept, is already used to treat people suffering from rheumatoid arthritis.

项目摘要/摘要。免疫细胞工程的最新进展彻底改变了血癌的治疗。遗传 T 细胞的修饰，其生理作用是杀死我们体内受感染和突变的细胞，嵌合抗原受体 (CAR) 可以重定向 T 细胞杀伤活性，以对抗表达某些表达的恶性细胞。靶向其表面的蛋白质。 CAR 是为了模仿生理性 T 细胞信号传导而构建的，其独特之处在于需要 T 细胞受体 (TCR) 和辅助受体（例如 CD28）提供的两种信号来诱导 T 细胞功能。最近针对多发性骨髓瘤 (MM)（一种常见的无法治愈的血癌）的临床研究表明 CAR T 细胞对于治疗对标准护理无反应的患者非常有效化疗。尽管如此，大多数 MM 患者在接受 CAR T 细胞治疗后一年内复发，其原因是他们的旧病复发并不明显。本次拨款申请中提出的项目的长期目标是利用我们的知识或 T 细胞信号传导使 CAR T 细胞疗法对 MM 更加有效。为此，我们有发现 CAR T 细胞上的内源性 CD28 破坏了它们杀死表达 CD28 刺激性的 MM 细胞的能力蛋白质 CD80 和 CD86。然而，相同的内源性 CD28 对于制造 CAR T 细胞至关重要，我们我们还发现，在 CAR T 细胞制造过程中提供的 CD28 信号有助于确定 CAR T 细胞的肿瘤杀手有多强大。拟议的研究旨在 1) 确定操纵 CD28 的方法 CAR T 细胞制造过程中的信号传导可以提高其杀死患者体内 MM 细胞的长期能力，以及 2) 确定内源性CD28信号传导如何导致CAR T细胞功能障碍。这些研究的结果将具有直接的临床意义，因为对 CAR T 细胞制造工艺的调整可能会迅速发生一种阻断 CD28 激活的药物阿巴西普 (abatacept) 已被用于治疗患有以下疾病的患者：类风湿关节炎。