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

超过80%的难治性弥漫性大B细胞淋巴瘤（DLBCL）患者对CD 19- 靶向嵌合抗原受体（CAR）T细胞疗法。然而，这些患者中有50%会复发。CD19 抗原丢失是B细胞急性淋巴细胞白血病（B-）中CD 19-CAR治疗失败的常见机制。 ALL），现在DLBCL患者也出现了类似的数据。CD 22是B细胞恶性肿瘤相关抗原 一项关于CD 22-CAR治疗的小型I期试验显示，即使在那些治疗失败的B-ALL患者中， CD 19-CAR疗法。有趣的是，在这些B-ALL患者中也观察到CD 22抗原逃逸。在临床前 在模型中，高抗原密度与最佳CAR T细胞应答相关，然而抗原的作用 密度对临床反应的影响尚未得到充分研究。这种CD 22-CAR疗法还没有被证实。 在难治性DLBCL患者中评估CD 22抗原密度对缓解和复发的影响 不明根据这些观察，弗兰克博士，血液和骨髓部门的讲师， 斯坦福大学的移植，在他的K 08申请中提出了研究新的CAR疗法 在DLBCL患者中，他正在接受强化训练计划，以准备开展独立的 翻译研究计划。Frank博士的培训计划侧重于开发临床试验中的额外技能 设计和管理;以及获得免疫学和生物信息学方法的先进专业知识。这 训练与他的三个研究目标很好地协调起来。他建议进行第一阶段试验， 这种CD 22-CAR疗法在难治性DLBCL患者中的安全性和有效性。第二，他希望 确定表面抗原密度是否影响接受CD 22-的患者的临床反应和复发 目前，CAR疗法和抗原逃避是否可以通过双特异性CD 19/CD 22-CAR疗法来减轻， 在DLBCL患者中进行研究。第三，他希望研究CAR T疗法如何影响 接受CD 22-CAR和CD 19/CD 22-CAR治疗的患者的循环肿瘤DNA（ctDNA）动力学， 优化治疗后监测策略。作为第三个目标的一部分，他建议使用一个斯坦福大学- 开发了ctDNA技术，CAPP-Seq，以鉴定与CAR疗法抗性相关的突变。到 监督弗兰克博士的培训和研究，他将由克里斯托·麦考尔博士和大卫·米克洛什博士指导， CAR-T细胞疗法的领先专家。此外，弗兰克博士还聘请了世界知名的罗纳德利维博士， 淋巴瘤和免疫疗法的领导者，以及ctDNA领域的领先专家Ash Alizadeh博士 技术，作为顾问和潜在的合作者，在他的培训和实现他的目标。在 在杰出导师弗兰克博士的指导下， 将有能力竞争R 01级的资金，发表高水平的论文，并推出一个独立的 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.