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

• 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
• 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

 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糖蛋白 (Dsg) 3 和 Dsg1 的自身抗体 (autoAbs) 引起的慢性且危及生命的水疱性疾病。如果不及时治疗，患者可能会因皮肤和/或粘膜严重起泡而死亡。目前的治疗依赖于一般免疫抑制来减少抗体的产生，这是有效的，但有致命感染的风险。例如，使用抗 CD20 单克隆 Ab 利妥昔单抗消除 B 细胞后，95% 的天疱疮患者出现水疱短期愈合，47% 的患者在治疗后疾病完全缓解。然而，约 80% 的患者会复发，这可能是由于 CD20+ B 细胞耗竭不完全所致，并且初始试验中 21 名患者中有 2 名出现严重感染，导致 1 人死亡。因此，理想的治疗方法是仅消除致病的自身免疫 B 细胞，而保留绝大多数有助于预防感染的 B 细胞。 近日，我院成功研发出嵌合T细胞受体（TCR）技术，用于癌症治疗。嵌合抗原受体 (CAR) 由与 T 细胞胞质信号结构域融合的癌症抗原胞外抗体组成。当在患者的 T 细胞上表达时，CAR 会引导这些 T 细胞杀死表达抗原的癌细胞，随后增殖产生记忆 CAR T 细胞，即使在难治性癌症患者中也能实现完全且持久的缓解。在这项提案中，我们将采用这项强大的技术来改造 T 细胞，杀死天疱疮中的自身免疫 B 细胞，从而实现自身免疫性疾病的完全和持久缓解。注定要分泌抗 Dsg3 或抗 Dsg1 Ab 的 B 细胞表达表面抗 Dsg Ab，专门标记天疱疮中的自身免疫 B 细胞。由于 B 细胞表面 autoAb 现在是靶标，因此我们逆转了典型的 CAR 设计，创建了嵌合 autoAb 受体 (CAAR)，其中 Dsg 抗原作为嵌合 TCR 的胞外结构域。该提案将检验以下假设：Dsg CAAR 将提供一种高效且安全的方法来杀死表达细胞表面抗 Dsg Ab 的 B 细胞，从而导致疾病缓解。完成该提案的目标将提供临床前数据来证明治疗试验的合理性 患者，以及我们在 CAR 技术和天疱疮方面独特的专业知识将有助于促进临床治疗的转化。这一提议既具有创新性又意义重大，因为这种方法从未在自身免疫性疾病中进行过测试，如果证明对天疱疮有效，则可以应用于已知靶抗原的任何自身抗体介导的疾病。