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: 10475725
• 负责人: Crystal Mackall
• 金额: $ 31.02万
• 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/10475725
• 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' 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

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：项目摘要/摘要 骨髓移植提供了第一个无可辩驳的证据，证明细胞治疗可以调节强大的和 持久的抗癌效果。基于这些开创性的观察，该领域一直在努力 了解并加强细胞介导的移植物抗肿瘤(GVT)效应 自体干细胞移植。尽管有这些努力，B细胞恶性肿瘤的GVT临床上仍有好处 仍然主要局限于接受剂量密集型移植条件调节的低负担疾病患者 然后输注自体或异体干细胞救援。自2011年首次观测以来，它已经 越来越清楚的是，通过基因工程表达嵌合抗原受体(CARS)的T细胞可以 介导对B细胞恶性肿瘤的强大和持久的影响，使癌症的细胞治疗成为可行的 治疗方式，即使对化疗难治、高负担疾病的患者也是如此。于是，CAR-T应运而生 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，长期以来 主导了干细胞移植方面的研究。很简单，这个项目寻求改善短期- 以CAR为基础的治疗B细胞恶性肿瘤的长期益处。B-ALL的经验已经确定了两个 CAR耐药的主要机制，似乎在很大程度上是相互排斥的：肿瘤因丢失而逃逸 或靶抗原表达减弱(通常发生在持续CAR-T存在的情况下 T细胞衰竭(通常发生在靶抗原持续表达的情况下)。AIM 1将测试 认为抗原水平是影响CD19-CAR疗效和复发的重要因素的假说 CD22-CAR用于DLBCL，并将测试第一辆进入临床的双特异性CAR的疗效，目标是 降低B-ALL和DLBCL中因抗原neg/lo变异引起的复发风险。AIM 2测试 假设“T细胞衰竭”是与T细胞衰竭相关的复发的主要原因。我们将寻求 确定可以区分其CAR T细胞容易耗尽的患者的预测性生物标志物， 并首次进行了最先进的单细胞TCR/RNA测序，以绘制持久性CAR T细胞的命运图 朝着“抗疲劳”的工程化嫁接的长期目标迈进一步。目标3开始解决一个主要问题 临床医生治疗CD19-CAR T细胞治疗DLBCL患者面临的实际挑战 是否应该接受自体或异体造血干细胞移植后的固定？“在以前的基础上构建 这项计划项目资助的成功演示了循环肿瘤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，作为后汽车巩固个性化分层的第一步 心理治疗。