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Engineering disease-specific T cells for pemphigus therapy

改造疾病特异性 T 细胞用于天疱疮治疗

基本信息

批准号：
9302670
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 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302670
关键词：
Adhesions Affinity Antigen Targeting Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process B-Lymphocytes Binding Biological Assay Bioluminescence Blood Bulla CD8-Positive T-Lymphocytes 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 Histology Human Hybridomas Immune Immunosuppression In Vitro Infection Injectable Institution Interferon Type II Interleukin-2 Interleukin-6 K-562 K562 Cells 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 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 fluorescence imaging healing in vivo innovation keratinocyte killings novel novel strategies pre-clinical public health relevance receptor relapse patients 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（由申请人提供）：寻常型天疱疮（PV）和落叶型天疱疮（PF）是由针对角质形成细胞粘附蛋白桥粒芯蛋白（Dsg）3和Dsg 1的自身抗体（自身抗体）引起的慢性和危及生命的起泡性疾病。如果不及时治疗，患者可能死于皮肤和/或粘膜的严重起泡。目前的治疗依赖于全身免疫抑制来减少Ab产生，这是有效的，但有致命感染的风险。例如，在用抗CD 20单克隆抗体利妥昔单抗去除B细胞后，95%的天疱疮患者经历水疱的短期愈合，47%的患者在停止治疗后达到疾病的完全缓解。然而，约80%的患者复发，可能是由于不完全的CD 20 + B细胞耗竭，并且在初始试验中的21名患者中有2名发生严重感染，导致1人死亡。因此，理想的治疗方法是只清除致病的自身免疫性B细胞，而不清除绝大多数有助于防止感染的B细胞。最近，嵌合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）由融合至T细胞胞质信号传导结构域的针对癌抗原的细胞外Ab组成。当在患者的T细胞上表达时，CAR指导这些T细胞杀死表达抗原的癌细胞，随后增殖以产生记忆CAR T细胞，从而导致即使在难治性癌症患者中也能完全和持久缓解。在这项提案中，我们将采用这种强大的技术来工程化T细胞，以使天疱疮中的自身免疫性B细胞活化，从而使自身免疫性疾病得到完全和持久的缓解。预定分泌抗Dsg 3或抗Dsg 1 Ab的B细胞表达表面抗Dsg Ab，特异性标记天疱疮中的自身免疫B细胞。由于B细胞表面自身抗体现在是靶标，我们逆转了典型的CAR设计以产生嵌合自身抗体受体（CAAR），其中Dsg抗原作为嵌合TCR的胞外结构域。该提议将检验Dsg CAAR将提供用于杀死表达细胞表面抗Dsg Ab的B细胞的高度有效和安全的手段，从而导致疾病缓解的假设。完成该提案的目的将提供临床前数据，以证明在以下方面进行治疗试验的合理性：患者，以及我们在CAR技术和天疱疮方面的独特专业知识将有助于促进转化为临床治疗。这一提议是创新的和重要的，因为这种方法从未在自身免疫性疾病中进行过测试，如果在天疱疮中证明有效，则可以应用于靶抗原已知的任何autoAb介导的疾病。