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，表明细胞疗法可以介导潜力和 持久的抗癌作用。基于这些第二个观察，该领域努力工作 在同种异体和 自体干细胞移植。尽管做出了这些努力，但GVT的临床受益于B细胞恶性肿瘤 仍然在很大程度上仅限于患有剂量强化移植调节的低烧伤疾病的患者 随后输注自体或同种异体干细胞救援。自2011年第一次观察以来， 越来越清楚地表明，通过基因设计以表达嵌合抗原受体（CAR）的T细胞可以 介导对B细胞恶性肿的潜在和持久作用，将癌症的细胞疗法作为可行 治疗方式，即使适用于化学危险，高烧伤疾病的患者。那是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扩展 在干细胞移植的背景下以主导的研究为主。非常简单，该项目试图改善短暂的 基于汽车的疗法对B细胞恶性肿的长期益处。 B-All的经验已经确定了两个 汽车阻力的主要机制，似乎在很大程度上是互斥的：肿瘤逃生 或靶向抗原的表达降低（通常发生在持续的CAR-T存在下 细胞）和T细胞衰竭（通常以靶向抗原的持续表达发生）。 AIM 1将测试 抗原水平是影响CD19卡车和继电器的重要因素的假设 DLBCL的CD22-CAR，并将测试第一辆双特异性汽车进入诊所的效率，目的是 降低了B-all和DLBCL中抗原负相关/LO变体引起的继电器风险。 AIM 2测试 假设“ T细胞耗尽”是与T细胞衰竭相关的继电器的主要原因。我们将寻求 确定可以区分汽车T细胞易于疲劳的患者的预测性生物标志物， 并进行最新的单细胞TCR/RNA测序以命运图持续的汽车T细胞，作为第一个 朝着工程移植的长期目标迈向“耗尽阻力”。 AIM 3开始解决专业 临床医生面临的实用挑战，治疗CD19卡车T细胞患者DLBCL的患者，即“患者 应该与自体或同种异体HSCT进行车后合并吗？”。 该计划项目授予的成功，以证明循环肿瘤DNA（CTDNA）在 预测B细胞恶性肿瘤的临床结果，我们将测试CTDNA是否可以预测结果 DLBCL的CD19卡车疗法，作为车后合并个性化分层的第一步 治疗。