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

淋巴瘤抗原密度和循环肿瘤 DNA 分析作为新型 CAR 疗法的决定因素

• 批准号: 10617260
• 负责人: Matthew J. Frank
• 金额: $ 16.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-09 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617260
• 关键词: Adult; Affect; Aftercare; Antigen Targeting; Antigens; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; Bioinformatics; Blood; Bone Marrow Transplantation; CAR T cell therapy; CD19 Antigens; CD19 gene; CD22 gene; CD58 gene; Cancer Personalized Profiling by Deep Sequencing; Cancer Vaccines; Clinical; Clinical Trials; Clinical Trials Design; Cytotoxic Chemotherapy; Data; Detection; Diagnosis; Disease Resistance; Dose; Down-Regulation; Early treatment; Eligibility Determination; Evaluation; Failure; Fine needle aspiration biopsy; Flow Cytometry; Funding; Futility; Genes; Genetic Fingerprintings; Genomic approach; Genomics; Goals; High-Throughput Nucleotide Sequencing; Immune response; Immunoglobulins; Immunology; Immunotherapy; Incidence; Individual; Lymphoma; Lymphoma cell; Malignant Neoplasms; Mentors; Mentorship; Methods; Monitor; Mutation; Non-Hodgkin' s Lymphoma; Paper; Patients; Phase; Plasma; Pre-Clinical Model; Prediction of Response to Therapy; Prognosis; Proteomics; Publishing; Recommendation; Recurrence; Refractory; Relapse; Research; Resistance; Role; Safety; Site; Surface Antigens; System; T cell response; Technology; Testing; Training; Training Programs; Treatment Failure; Treatment outcome; United States; Universities; Woman; appropriate dose; career; chimeric antigen receptor; chimeric antigen receptor T cells; cohort; density; determinants of treatment resistance; effective therapy; experience; instructor; large cell Diffuse non-Hodgkin' s lymphoma; men; neoplastic cell; novel; novel therapeutics; outcome prediction; phase I trial; predicting response; programmed cell death ligand 1; receptor function; recruit; relapse patients; response; safety and feasibility; safety assessment; skills; success; surveillance strategy; targeted treatment; translational research program; treatment response; tumor; tumor DNA

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.

超过80%的难治性弥漫性大b细胞淋巴瘤（DLBCL）患者对CD19-有应答