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。

基本信息

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
项目类别：
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

项目摘要

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我们和其他人在 B 细胞恶性肿瘤患者中的完全缓解 (CR) 率超过 90%。患有复发/难治性 (r/r) ALL 的患者中，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 患者。用抗CD19 CAR T细胞治疗CLL，完全缓解率较低，为20-25%，但治疗后复发此外，还有许多B细胞恶性肿瘤患者无法缓解。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。 T细胞计数低的患者和婴儿时期的患者此外，一些患者之前会迅速进展。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 细胞内在和外在的因素来验证这种已经转化的方法的可行性我们将采取耐药机制以及所有导致复发的细胞内在机制。与具有基因专业知识的核心实验室已经建立的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。设计研究以了解 CD19 阴性和 CD19 的生物学和机制在慢性淋巴细胞白血病（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为此，我们将利用我们独特的样本库。超过 200 名患者在儿童医院和宾夕法尼亚大学接受了 CTL019 的治疗。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）是预制的“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。可以跨越 HLA 屏障使用，不会引起 GVHD 或被快速排斥，因此，它们可以解决这一问题。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 ii) 未能收集足够的 T 细胞或制造自体 CAR 细胞；和 iii) 自体 CTL019 未能诱导 B 细胞再生障碍和/或临床反应。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。