Project 4: Enhancing the Efficacy of Chimeric Antigen Receptor Therapy for B-ALL and DLBCL

项目4：增强嵌合抗原受体治疗B-ALL和DLBCL的疗效

基本信息

批准号：
10242110
负责人：
Crystal Mackall
金额：
$ 31.65万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-05-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242110
关键词：
Address Adoptive Transfer Allogenic Antigen Targeting Antigens Autologous Autologous Stem Cell Transplantation B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia Bar Codes Biological Blood Component Removal Bone Marrow Transplantation CAR T cell therapy CD19 Antigens CD19 gene CD22 gene Cancer Personalized Profiling by Deep Sequencing Cell Therapy Cell surface Cells Clinic Clinical Clonal Evolution Consolidation Therapy Data Disease Disease remission Dose Engineering Epitopes Failure Generations Goals Graft-Versus-Tumor Induction Immune Immunotherapy Impairment In complete remission Infusion procedures Laboratories Lymphoma Maintenance Malignant Neoplasms Maps Measures Mediating Modality Monitor Mutation Outcome Patients Program Research Project Grants Recurrence Relapse Research Residual Neoplasm Resistance Role Seminal Specificity Stem cell transplant Stratification T cell receptor repertoire sequencing T-Cell Activation T-Lymphocyte Testing Therapeutic Time Translating Transplantation Conditioning Tumor Escape Tumor Immunity Variant Work alpha-beta T-Cell Receptor anti-cancer anti-tumor immune response antitumor effect base burden of illness cancer therapy cell free DNA cell mediated immune response chimeric antigen receptor chimeric antigen receptor T cells design disorder control efficacy testing exhaustion experience genetic signature genetically modified cells graft vs leukemia effect high dimensionality improved large cell Diffuse non-Hodgkin&apos s lymphoma leukemia/lymphoma novel novel marker outcome prediction patient subsets predict clinical outcome predictive marker prognostic receptor function regenerative relapse risk resistance mechanism response stem cells success transcriptome sequencing tumor tumor DNA

项目摘要

Project 4: Project Summary/Abstract Bone marrow transplantation provided the first irrefutable evidence that cell therapy can mediate potent and long-lasting anti-cancer effects. Based upon these seminal observations, the field has worked diligently to understand and enhance cell mediated graft-versus-tumor (GVT) effects in the context of allogeneic and autologous stem cell transplantation. Despite these efforts, clinical benefit from GVT in B cell malignancies remains largely limited to patients with low burden disease who undergo dose intensive transplant conditioning following by infusion of autologous or allogeneic stem cell rescue. Since the first observation in 2011, it has become increasingly clear that T cells genetically engineered to express chimeric antigen receptors (CARs) can mediate potent and durable effects against B cell malignancies, establishing cell therapy for cancer as a viable therapeutic modality, even for patients with chemorefractory, high burden disease. Thus, emergence of CAR-T cell therapies is a natural extension of the efforts to harness cell based anti-tumor immunity that has long dominated research in the context of stem cell transplantation. Very simply, this Project seeks to improve short- and long-term benefit of CAR based therapies for B cell malignancies. Experience in B-ALL has identified two major mechanisms of CAR resistance, which appear to be largely mutually exclusive: tumor escape due to loss or diminished expression of the targeted antigen (which typically occurs in the presence of persistent CAR-T cells) and T cell failure (which typically occurs with continued expression of the targeted antigen). Aim 1 will test the hypothesis that antigen level is an important factor impacting response and relapse following CD19-CAR and CD22-CAR for DLBCL, and will test the efficacy of the first bispecific CAR to enter the clinic, with the goal of diminishing the risk of relapse due to antigen neg/lo variants in both B-ALL and DLBCL. Aim 2 tests the hypothesis that “T cell exhaustion” is the major cause of relapse associated with T cell failure. We will seek to identify predictive biomarkers that can distinguish patients whose CAR T cells are predisposed to exhaustion, and undertake state-of-the-art single cell TCR/RNA sequencing to fate map persistent CAR T cells, as a first step toward a long-term goal of engineering grafts for “exhaustion resistance”. Aim 3 begins to address a major practical challenge facing clinicians treating patients with CD19-CAR T cells for DLBCL, namely “which patients should undergo post-CAR consolidation with autologous or allogeneic HSCT?”. Building upon previous successes in this Program Project Grant in demonstrating the utility of circulating tumor DNA (ctDNA) in predicting clinical outcomes for B cell malignancies, we will test whether ctDNA can predict outcomes following CD19-CAR therapy for DLBCL, as a first step toward personalized stratification of post-CAR consolidation therapy.

项目 4：项目总结/摘要骨髓移植提供了第一个无可辩驳的证据，证明细胞疗法可以介导有效和有效的治疗。基于这些开创性的观察，该领域一直在努力研究。了解并增强同种异体背景下细胞介导的移植物抗肿瘤（GVT）效应尽管做出了这些努力，GVT 在 B 细胞恶性肿瘤中仍具有临床益处。仍然主要限于接受剂量密集移植调理的低负荷疾病患者自2011年首次观察以来，随后进行了自体或同种异体干细胞输注。越来越清楚的是，通过基因工程改造来表达嵌合抗原受体（CAR）的 T 细胞可以介导针对 B 细胞恶性肿瘤的有效且持久的作用，使细胞疗法成为一种可行的癌症治疗方法治疗方式，甚至适用于化疗难治性、高负担疾病的患者。因此，CAR-T 的出现。细胞疗法是利用基于细胞的抗肿瘤免疫的努力的自然延伸，这种免疫长期以来一直存在干细胞移植领域的主导研究非常简单，该项目旨在改善短期问题。基于 CAR 的疗法治疗 B 细胞恶性肿瘤的长期益处已确定为 B-ALL 的两个方面。 CAR 耐药的主要机制似乎在很大程度上是相互排斥的：由于丢失而导致肿瘤逃逸或目标抗原表达减少（通常发生在持续存在 CAR-T 的情况下）细胞）和 T 细胞衰竭（通常在目标抗原持续表达时发生）。假设抗原水平是影响 CD19-CAR 后反应和复发的重要因素， CD22-CAR用于DLBCL，并将测试第一个进入临床的双特异性CAR的疗效，目标降低 B-ALL 和 DLBCL 中抗原 neg/lo 变异导致的复发风险。假设“T 细胞衰竭”是与 T 细胞衰竭相关的复发的主要原因。识别预测性生物标志物，可以区分 CAR T 细胞易衰竭的患者，并进行最先进的单细胞 TCR/RNA 测序，以绘制持久性 CAR T 细胞的命运图谱，这是第一个朝着“抗疲劳”工程移植的长期目标迈出了一步，目标 3 开始解决一个主要问题。使用 CD19-CAR T 细胞治疗 DLBCL 患者面临的实际挑战，即“哪些患者应该在之前的基础上进行自体或同种异体 HSCT 的 CAR 后巩固吗？”。该计划项目拨款成功展示了循环肿瘤 DNA (ctDNA) 在预测 B 细胞恶性肿瘤的临床结果，我们将测试 ctDNA 是否可以预测以下结果 CD19-CAR 治疗 DLBCL，作为 CAR 后巩固个性化分层的第一步治疗。