Project 1: Overcoming resistance of B cell leukemia to CD19 CAR T Cells.

项目1：克服B细胞白血病对CD19 CAR T细胞的耐药性。

• 批准号: 10245063
• 负责人: DAVID L PORTER
• 金额: $ 41.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245063
• 关键词: Ablation; Address; Allogenic; Autologous; B lymphoid malignancy; B-Cell Leukemia; B-Lymphocytes; Biological Specimen Banks; Biology; CAR T cell therapy; CD19 gene; CD22 gene; CRISPR/Cas technology; Cell Count; Cell physiology; Cells; Cellular immunotherapy; Cessation of life; Childhood Acute Lymphocytic Leukemia; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Cytotoxic T-Lymphocytes; Data; Defect; Detection; Disease; Disease remission; Exhibits; Failure; Genes; Genetic; Hematologic Neoplasms; Immunosuppression; Immunotherapeutic agent; In Vitro; In complete remission; Infant; Infusion procedures; Laboratories; Lead; Leukemic Cell; Malignant Neoplasms; Medical; Methods; Mission; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Phenotype; Play; Prior Therapy; Proliferating; Public Health; RNA Splicing; Refractory; Relapse; Research; Research Design; Resistance; Risk; Role; Science; Specificity; T cell therapy; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Translating; Variant; base; checkpoint inhibition; chimeric antigen receptor; design; effective therapy; experimental study; high risk; improved; in vivo; innovation; mouse model; neoplastic cell; novel strategies; phase I trial; pre-clinical; predictive marker; programmed cell death protein 1; receptor; relapse risk; research clinical testing; resistance mechanism; response; safety and feasibility; success; transcription activator-like effector nucleases; tumor microenvironment

SUMMARY (PROJECT 1) Anti-CD19 chimeric antigen receptor redirected T cells (CART-19) have been dramatically successful for some patients with B-cell malignancies. We and others have shown complete response (CR) rates of over 90% in patients with relapsed/refractory (r/r) ALL. Many of these remissions are sustained, but the major limitation is relapse in 20-50% of patients and two-thirds of these relapses involve CD19-negative ALL. In patients with r/r CLL treated with anti-CD19 CAR T cells, complete response rates are lower at 20-25%, but relapse after remission is very unusual. In addition, there are also many patients with B cell malignancies who cannot benefit from CAR T cells because of the inability to collect or manufacture T cells, especially from intensively treated patients with low T cell counts and from infants. In addition, some patients will rapidly progress before manufacturing is complete and cannot tolerate or survive the necessary treatment delay. This project will use a comprehensive strategy to target the major limitations in CAR T cell therapy, increasing the feasibility of this already transformational approach by looking both at T cell-intrinsic and extrinsic mechanisms of resistance as well as ALL cell-intrinsic mechanisms that lead to relapse. We will take advantage of already established successful collaborations with core laboratories with expertise in gene editing, as well as state of the art correlative science to explore a number of innovative aims. We have designed studies to understand the biology and mechanisms underlying both CD19 negative and CD19 positive relapse in ALL. In CLL, where response rates are a more significant barrier than relapse, we will explore the role that checkpoint molecules, the tumor microenvironment, and the leukemia cell itself plays in inducing resistance to CTL019. To do this, we will capitalize on our unique bank of specimens derived from over 200 patients treated at Children's Hospital and U Penn with CTL019. Finally, we have designed high impact clinical trials 1) testing methods to limit CD19 negative relapse in ALL (by targeting CD19 and CD22 concurrently) and 2) enhancing responses in B cell malignancies by testing gene-edited, CAR modified allogeneic T cells (“PACE” CARs). PACE CARs are pre-manufactured, “universal donor” CAR+ cells that are gene-edited with CRISPR technology to eliminate T cell receptors and HLA class I molecules. These cells could be used across HLA barriers and should not cause GVHD or be rapidly rejected. Therefore, they can solve unmet medical needs in autologous CAR therapy where i) there is a high degree of clinical urgency (cells are immediately available); ii) there has been a failure to collect adequate T cells or manufacture autologous CAR cells; and iii) where autologous CTL019 has failed to induce B cell aplasia and/or clinical response. This research will be highly significant because it will lead to detailed understanding of mechanisms of resistance to CTL019, provide information that can be rapidly translated for clinical testing, and perform highly innovative clinical trials attempting to enhance outcomes for patients who currently have no effective treatment options.

摘要（项目 1） 抗 CD19 嵌合抗原受体重定向 T 细胞 (CART-19) 在某些方面取得了巨大成功 患有 B 细胞恶性肿瘤的患者。我们和其他人已经显示出超过 90% 的完全缓解 (CR) 率 复发/难治性 (r/r) ALL 患者。其中许多缓解是持续的，但主要限制是 20-50% 的患者会出现复发，其中三分之二的复发涉及 CD19 阴性 ALL。对于患有 r/r 的患者 用抗CD19 CAR T细胞治疗CLL，完全缓解率较低，为20-25%，但治疗后复发 缓解是非常不寻常的。此外，还有很多B细胞恶性肿瘤患者无法 由于无法收集或制造 T 细胞，尤其是从密集型 T 细胞中获益，因此可以从 CAR T 细胞中获益。 接受治疗的 T 细胞计数低的患者和婴儿患者。此外，一些患者在发病前会迅速病情进展。 制造已完成，无法容忍或经受必要的治疗延迟。 该项目将采用综合策略来针对 CAR T 细胞疗法的主要局限性，增加 通过观察 T 细胞内在和外在因素来验证这种已经转化的方法的可行性 耐药机制以及导致复发的所有细胞内在机制。我们将采取 与拥有基因专业知识的核心实验室建立成功合作的优势 编辑以及最先进的相关科学来探索许多创新目标。我们有 设计研究以了解 CD19 阴性和 CD19 的生物学和机制 ALL 阳性复发。在 CLL 中，缓解率是比复发更重要的障碍，我们将 探索检查点分子、肿瘤微环境和白血病细胞本身在 诱导对CTL019的抗性。为此，我们将利用我们独特的样本库，这些样本来自 超过 200 名患者在儿童医院和宾夕法尼亚大学接受了 CTL019 治疗。最后我们设计了高 影响临床试验 1) 限制 ALL 中 CD19 阴性复发的测试方法（通过靶向 CD19 和 CD22） 同时）和 2）通过测试基因编辑、CAR 修饰来增强 B 细胞恶性肿瘤的反应 同种异体 T 细胞（“PACE”CAR）。 PACE CAR 是预制的“通用供体”CAR+ 细胞， 使用 CRISPR 技术进行基因编辑，消除 T 细胞受体和 HLA I 类分子。这些细胞可以 可以跨越 HLA 屏障使用，并且不会引起 GVHD 或迅速被排斥。因此，他们可以解决 自体 CAR 疗法中未满足的医疗需求，其中 i) 具有高度的临床紧迫性（细胞是 立即可用）； ii) 未能收集足够的 T 细胞或制造自体 CAR 细胞； iii) 自体 CTL019 未能诱导 B 细胞再生障碍和/或临床反应。这 研究将非常重要，因为它将导致对耐药机制的详细了解 CTL019，提供可快速转化用于临床检测的信息，并进行高度创新 临床试验试图提高目前没有有效治疗方案的患者的治疗效果。