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液癌的治疗。遗传 T细胞的修饰，其生理作业是杀死整个身体的感染和突变细胞，嵌合抗原受体（CAR）可以重新定向T细胞对表达某些表达某些恶性细胞的杀死活性靶蛋白在其表面上。汽车是为模仿生理T细胞信号传导而制造的，这在其它的独特对T细胞受体（TCR）和CD28等共受体提供的两个信号的要求，以诱导T 细胞功能。常见无法治愈的血液癌多发性骨髓瘤（MM）最近的临床研究已表明该汽车T细胞非常有效地治疗对护理标准不反应的患者化学疗法。尽管如此，大多数MM患者在CAR T细胞疗法的一年内复发他们的复发并不明显。本赠款申请中提出的项目的长期目标是使用我们的知识或T细胞信号传导使MM有效的CAR T细胞疗法更有效。为此，我们有发现汽车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。但是，相同的内源性CD28对于制造CAR T细胞至关重要，我们还发现在汽车T细胞制造过程中提供的CD28信号有助于确定肿瘤杀手的汽车T细胞变得多么好。拟议的研究寻求1）确定操纵CD28的方法汽车T细胞制造过程中的信号传导可以提高其长期杀死患者MM细胞的能力，并且 2）确定内源性CD28信号如何引起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细胞制造过程的调整可能会很快实施和阻止CD28激活的药物Abatacept已被用来治疗患有患者的人类风湿关节炎。