Engineering disease-specific T cells for pemphigus therapy

工程化疾病特异性 T 细胞用于天疱疮治疗

基本信息

批准号：
8937451
负责人：
Aimee S Payne
金额：
$ 35.15万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-07 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8937451
关键词：
Adhesions Affinity Antigen Targeting Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process B-Lymphocytes Binding Biological Assay Bioluminescence Blood Bulla CD8B1 gene Cancer Patient Cell Surface Proteins Cell surface Cells Cessation of life Chronic Clinical Clinical Data Complex Cytolysis Data Disease Disease remission Electroporation Engineering Engraftment Enzyme-Linked Immunosorbent Assay Extracellular Domain Fc Receptor Fluorescence Microscopy Healed Histology Human Hybridomas Image Immune Immunosuppression In Vitro Infection Institution Interferon Type II Interleukin-2 Interleukin-6 K-562 K562 Cells Lead Left Length Life MS4A1 gene Malignant Neoplasms Mediating Memory Modeling Monitor Mucous Membrane Mus PTPRC gene Patients Pemphigus Pemphigus Vulgaris Peripheral Blood Mononuclear Cell Phase Procedures Production Proliferating Proteins RNA Receptor Signaling Refractory Relapse Relative (related person)Resistance Risk Safety Serum Signal Transduction Skin Surface System T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Therapeutic Trials Toxic effect Translations Transplantation Xenograft procedure base bioluminescence imaging cancer cell cancer therapy cell killing cell type chimeric antigen receptor cytokine design desmoglein desmoglein III experience extracellular healing in vivo innovation keratinocyte killings novel novel strategies pre-clinical public health relevance receptor rituximab

项目摘要

DESCRIPTION (provided by applicant): Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are chronic and life-threatening blistering diseases caused by autoantibodies (autoAbs) to the keratinocyte adhesion proteins desmoglein (Dsg) 3 and Dsg1. Left untreated, patients can die from severe blistering of the skin and/or mucous membranes. Current therapy relies on general immune suppression to reduce Ab production, which is effective but risks fatal infection. For example, after B cell depletion with the anti-CD20 monoclonal Ab rituximab, 95% of pemphigus patients experience short-term healing of blisters and 47% achieve complete remission of disease off therapy. However, ~80% of patients relapse, likely due to incomplete CD20+ B cell depletion, and two of 21 patients in the initial trial had serious infections, resultig in one death. Thus, the ideal therapy would eliminate only the disease-causing autoimmune B cells, sparing the vast majority of B cells that help protect against infection. Recently, chimeri T cell receptor (TCR) technology was successfully developed at our institution for cancer therapy. A chimeric antigen receptor (CAR) consists of an extracellular Ab to a cancer antigen fused to T cell cytoplasmic signaling domains. When expressed on the patient's T cells, the CAR directs those T cells to kill antigen-expressing cancer cells and subsequently proliferate to produce memory CAR T cells, leading to complete and durable remission even in refractory cancer patients. In this proposal, we will adapt this powerful technology to engineer T cells to kil autoimmune B cells in pemphigus in order to produce complete and durable remission of autoimmune disease. B cells destined to secrete anti-Dsg3 or anti-Dsg1 Abs express surface anti-Dsg Ab, specifically marking the autoimmune B cells in pemphigus. Because the B cell surface autoAb is now the target, we reversed the typical CAR design to create a chimeric autoAb receptor (CAAR), with the Dsg antigen as the extracellular domain of the chimeric TCR. This proposal will test the hypothesis that Dsg CAARs will provide a highly effective and safe means for killing B cells expressing cell surface anti- Dsg Ab, resulting in disease remission. Completing the aims of the proposal will provide pre-clinical data to justify therapeutic trials in patients, and our unique expertise in CAR technology and pemphigus will help facilitate translation to clinical therapy. This proposal is both innovative and significant because such an approach has never been tested in autoimmune disease and, if proven effective in pemphigus, could be applied to any autoAb-mediated disease for which the target antigen is known.

描述（由适用提供）：pemphigus ulggaris（PV）和Pemphigus叶子（PF）是由自身抗体（自动抗体）引起的慢性且威胁生命的泡沫疾病，可引起角质形成细胞粘附蛋白（DSG）3和DSG1。剩下的未治疗，患者可能因皮肤和/或粘膜的严重起泡而死亡。当前的治疗依赖于一般的免疫抑制来减少AB产生，这是有效的，但风险会致命感染。例如，在与抗CD20单克隆AB利妥昔单抗进行B细胞部署后，有95％的Pemphigus患者经历了水泡的短期愈合，而47％的患者可以完全缓解疾病的完全缓解。但是，约80％的患者继电器可能是由于不完全的CD20+ B细胞部署引起的，而在初次试验中21例患者中有2例患有严重的感染，导致死亡。这是理想的疗法只能消除引起疾病的自身免疫性B细胞，从而占据帮助防止感染的绝大多数B细胞。最近，Chimeri T细胞受体（TCR）技术在我们的癌症治疗机构成功开发。嵌合抗原受体（CAR）由与T细胞胞质信号传导域融合的细胞外AB组成。当在患者的T细胞上表达时，CAR指示这些T细胞杀死表达抗原的癌细胞，然后随后增殖以产生记忆CAR T细胞，即使在难治性的癌症患者中，也会导致完整而持久的缓解。在此提案中，我们将适应这种强大的技术来设计T细胞，以杀死Pempigus中的自身免疫性B细胞，以产生自身免疫性疾病的完全耐用的缓解。 B细胞注定要分泌抗DSG3或抗DSG1 ABS ABS表达表面抗DSG AB，特别标记了Pempigus中的自身免疫性B细胞。由于B细胞表面自动AutoAb现在是目标，因此我们逆转了典型的汽车设计，以创建嵌合自动驾驶仪受体（CAAR），而DSG抗原是嵌合TCR的细胞外结构域。该提案将检验以下假设：DSG CAARS将为杀死表达细胞表面抗DSG AB的B细胞的高效和安全手段，从而导致疾病缓解。完成该提案的目的将提供临床前数据，以证明在患者以及我们在汽车技术和Pempigus方面的独特专业知识将有助于促进转化为临床疗法。该提案既具有创新性又具有重要意义，因为这种方法从未在自身免疫性疾病中进行过测试，并且如果证明对Pempigus有效，可以将其应用于任何已知靶抗原的自动启动介导的疾病。