Engineering disease-specific T cells for pemphigus therapy

 描述(申请人提供)：寻常型天疱疮(PV)和叶型天疱疮(PF)是由角质形成细胞黏附蛋白Desmoglein(DSG)3和DSG1的自身抗体(AutoAbbs)引起的慢性和危及生命的水泡性疾病。如果不进行治疗，患者可能会死于皮肤和/或粘膜的严重水泡。目前的治疗方法依赖于全身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，在使用抗CD20单抗美妥昔单抗去除B细胞后，95%的天疱疮患者水泡短期愈合，47%的天疱疮患者停止治疗后病情完全缓解。然而，约80%的患者复发，可能是由于CD20+B细胞不完全耗尽，最初试验的21名患者中有2名发生严重感染，导致1名死亡。因此，理想的治疗方法应该只清除致病的自身免疫B细胞，而保留绝大多数有助于预防感染的B细胞。最近，我们癌症治疗研究所成功地开发了嵌合体T细胞受体(TCR)技术。嵌合抗原受体(CAR)由抗癌抗原的胞外抗体与T细胞胞浆信号域融合而成。当CAR在患者的T细胞上表达时，它会指示这些T细胞杀死表达抗原的癌细胞，然后增殖产生记忆CAR T细胞，即使在难治性癌症患者中也能导致完全和持久的缓解。在这项提案中，我们将采用这项强大的技术来改造T细胞，以杀死天疱疮中的自身免疫B细胞，以产生完全和持久的自身免疫性疾病的缓解。分泌抗Dsg3或抗DSG1抗体的B细胞表达表面抗DSG抗体，特异性地标记天疱疮中的自身免疫B细胞。由于B细胞表面的AutoAb现在是靶标，我们逆转了典型的CAR设计，创建了嵌合的AutoAb受体(CAAR)，将DSG抗原作为嵌合TCR的胞外域。这项建议将检验这样一种假设，即DSG CAARs将提供一种高效且安全的方法来杀伤表达细胞表面抗DSG抗体的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，以证明在 我们在CAR技术和天疱疮方面的独特专业知识将有助于将其转化为临床治疗。这一建议既具有创新性，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，如果被证明对天疱疮有效，则可以应用于任何已知靶抗原的自身抗体介导的疾病。

 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.