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

• 批准号: 10700010
• 负责人: Crystal Mackall
• 金额: $ 31.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10700010
• 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; Refractory; Relapse; Reproducibility; 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; 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' s lymphoma; leukemia/lymphoma; novel; novel marker; outcome prediction; patient subsets; predict clinical outcome; predictive marker; prognostic; regenerative; relapse risk; resistance mechanism; response; stem cells; success; transcriptome sequencing; tumor; tumor DNA

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。 长效抗癌作用。基于这些开创性的观察，该领域一直在努力工作 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 自体干细胞移植。尽管做出了这些努力，GVT 在 B 细胞恶性肿瘤中的临床获益 仍然主要限于接受剂量密集移植调理的低负荷疾病患者 随后输注自体或同种异体干细胞救援。自 2011 年首次观测以来， 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，即使对于患有化疗难治性高负担疾病的患者也是如此。于是，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 主导了干细胞移植领域的研究。很简单，该项目旨在改善短期 以及基于 CAR 的 B 细胞恶性肿瘤疗法的长期益处。 B-ALL 的经验确定了两种 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（通常随着目标抗原的持续表达而发生）。目标 1 将进行测试 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。目标 2 测试 假设“T 细胞耗竭”是与 T 细胞衰竭相关的复发的主要原因。我们将寻求 识别预测生物​​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”工程移植物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 患者的临床医生面临的实际挑战，即“哪些患者 应该通过自体或同种异体 HSCT 进行 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。