Lymphoma Antigen Density and Circulating Tumor DNA Profiling As Determinants of Novel CAR Therapies

80%以上的难治性弥漫大B细胞淋巴瘤(DLBCL)患者对CD19- 靶向嵌合抗原受体(CAR)T细胞治疗。然而，这些患者中有50%会复发。CD19 抗原丢失是CD19-CAR治疗B细胞急性淋巴细胞白血病失败的常见机制。 ALL)，类似的数据现在也出现在DLBCL患者身上。CD22是一种B细胞恶性肿瘤相关抗原 CD22-CAR疗法的一个小型I期试验显示，即使在那些失败的患者中，B-ALL也是有希望的 CD19-汽车疗法。有趣的是，在这些B-ALL患者中也可以看到CD22抗原逃逸。在临床前阶段 模型中，高抗原密度与最佳CAR T细胞反应相关，然而抗原的作用 密度对临床反应的影响还没有得到充分的研究。这种CD22-CAR疗法还没有 难治性DLBCL患者的评估及CD22抗原密度对疗效和复发的影响 是未知的。基于这些观察，血液和骨髓科的讲师弗兰克博士 在斯坦福大学移植，在他的K08申请中提出了研究新的汽车疗法 在DLBCL患者接受强化训练计划的同时，为他启动独立的 翻译研究计划。弗兰克博士的培训计划侧重于在临床试验中发展更多技能 设计和管理；以及在免疫学和生物信息学方法方面获得先进的专业知识。这 培训将很好地与他的三个研究目标相协调。他提议进行一项第一阶段的审判调查 CD22-CAR治疗难治性DLBCL的安全性和有效性。第二，他希望 确定表面抗原密度是否影响接受CD22的患者的临床应答和复发 CAR疗法以及双特异性CD19/CD22-CAR疗法是否可以减轻抗原逃避，目前 在DLBCL患者中进行调查。第三，他希望研究CAR-T疗法是如何影响 接受CD22-CAR和CD19/CD22-CAR治疗的患者循环肿瘤DNA(CtDNA)动态变化 优化治疗后监测策略。作为第三个目标的一部分，他提议使用斯坦福- 开发了ctDNA技术CAPP-Seq，以确定与CAR治疗耐药相关的突变。至 监督弗兰克博士的培训和研究，他将得到克里斯托·麦考尔博士和大卫·米克洛斯博士的指导， CAR T细胞治疗领域的顶尖专家。此外，弗兰克博士还聘请了世界知名的罗纳德·利维博士 淋巴瘤和基于免疫的治疗的领导者，以及ctDNA的领先专家Ash Alizadeh博士 在他的培训和实现他的目标的过程中，担任顾问和潜在的合作者。在……里面 在杰出导师弗兰克博士的指导下执行他提出的研究和培训计划 将为竞争R01级别的资金，发表高水平的论文，并推出独立 领导翻译研究项目的职业生涯。

More than 80% of patients with refractory diffuse large B-cell lymphoma (DLBCL) respond to CD19- targeting chimeric antigen receptor (CAR) T cell therapy. Yet, 50% of these patients will relapse. CD19 antigen loss is a common mechanism for CD19-CAR therapy failure in B-cell acute lymphoblastic leukemia (B- ALL), and similar data is now emerging for DLBCL patients. CD22 is a B-cell malignancy associated antigen and a small Phase I trial of CD22-CAR therapy has shown promise in B-ALL even in those patients who failed CD19-CAR therapy. Interesting, CD22 antigen escape was also seen in these B-ALL patients. In preclinical models, high antigen density was associated with optimal CAR T cell response, however the role of antigen density's impact on clinical response has not been fully investigated. This CD22-CAR therapy has yet to be evaluated in refractory DLBCL patients and the role of CD22 antigen density's impact on response and relapse is unknown. Based on these observations, Dr. Frank, an Instructor in the Division of Blood and Marrow Transplantation at Stanford University, has proposed in his K08 application to investigate novel CAR therapies in DLBCL patients while undergoing an intensive training program to prepare him to launch an independent translational research program. Dr. Frank's training plan focuses on developing additional skills in clinical trial design and management; and in gaining advanced expertise in immunology and bioinformatic methods. This training will nicely harmonize with his three research aims. He proposes to conduct a Phase I trial investigating the safety and efficacy of this CD22-CAR therapy in patients with refractory DLBCL. Second, he wishes to determine whether surface antigen density impacts clinical response and relapse for patients receiving CD22- CAR therapy and whether antigen evasion can be mitigated by a bispecific CD19/CD22-CAR therapy, currently being investigated in DLBCL patients. Third, he desires to investigate how CAR T therapy influences circulating tumor DNA (ctDNA) dynamics in patients undergoing CD22-CAR and CD19/CD22-CAR therapy to optimize post-treatment surveillance strategies. As part of this third aim, he proposes to use a Stanford- developed ctDNA technology, CAPP-Seq, to identify mutations associated with CAR therapy resistance. To oversee Dr. Frank's training and research, he will be mentored by Drs. Crystal Mackall and David Miklos, leading experts in CAR T cell therapy. In addition, Dr. Frank has recruited Dr. Ronald Levy, a world-renowned leader in lymphoma and immune-based therapies, and Dr. Ash Alizadeh, a leading expert in ctDNA technologies, to serve as advisors and potential collaborators in his training and in accomplishing his aims. In carrying out his proposed research and training plan under the guidance of outstanding mentorship, Dr. Frank will be equipped to compete for R01 level of funding, publish high-level papers, and to launch an independent career leading a translational research program.