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: 9982243
• 负责人: DAVID L PORTER
• 金额: $ 34.05万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982243
• 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.

概要（项目1） 抗CD 19嵌合抗原受体重定向的T细胞（CART-19）已经在一些人中取得了巨大的成功。 B细胞恶性肿瘤患者。我们和其他人已经显示完全缓解（CR）率超过90%， 复发/难治性（r/r）ALL患者。许多缓解是持续的，但主要的限制是 20-50%的患者复发，其中三分之二的复发涉及CD 19阴性ALL。r/r患者 用抗CD 19 CAR T细胞治疗的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，也有许多B细胞恶性肿瘤患者不能 由于不能收集或制造T细胞，特别是从密集的 治疗低T细胞计数的患者和婴儿。此外，有些患者会在发病前迅速进展， 制造完成并且不能容忍或经受住必要的治疗延迟。 该项目将使用全面的策略来针对CAR T细胞治疗的主要局限性， 通过观察T细胞-内在和外在， 耐药机制以及导致复发的ALL细胞内在机制。我们将采取 与具有基因工程专业知识的核心实验室成功合作的优势 编辑，以及最先进的相关科学，探索了一些创新的目标。我们有 设计研究以了解CD 19阴性和CD 19阴性的生物学和机制。 ALL复发阳性。在CLL中，缓解率是比复发更重要的障碍， 探索检查点分子、肿瘤微环境和白血病细胞本身在白血病中的作用。 诱导对CTL 019的抗性。为此，我们将利用我们独特的标本库， 超过200名患者在儿童医院和U Penn接受了CTL 019治疗。最后，我们设计了高 影响临床试验1）限制ALL中CD 19阴性复发的测试方法（通过靶向CD 19和CD 22 同时）和2）通过测试基因编辑的CAR修饰的细胞增强B细胞恶性肿瘤的反应 同种异体T细胞（“PACE”汽车）。PACE汽车是预先制造的“通用供体”CAR+细胞， 使用CRISPR技术进行基因编辑，以消除T细胞受体和HLA I类分子。这些细胞可以 应跨越HLA屏障使用，不应引起GVHD或迅速排斥。因此，他们可以解决 在自体CAR疗法中未满足的医疗需求，其中i）存在高度的临床紧迫性（细胞是 ii）未能收集足够的T细胞或制造自体CAR 细胞;和iii）其中自体CTL 019未能诱导B细胞再生障碍和/或临床应答。这 研究将是非常重要的，因为它将导致详细了解耐药机制， CTL 019，为临床测试提供可快速翻译的信息，并具有高度创新性 临床试验试图改善目前没有有效治疗选择的患者的结果。