CD19 Directed CAR Therapy

CD19定向CAR疗法

• 批准号: 8601689
• 负责人: CARL H. JUNE
• 金额: $ 48.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-12 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601689
• 关键词: Address; Adult; Adverse effects; Aftercare; Allogeneic Bone Marrow Transplantation; Allogeneic Lymphocyte; Allogenic; Antibodies; Antigen Receptors; Autologous; B lymphoid malignancy; B-Lymphocytes; Biological Monitoring; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; CD19 gene; CD3 Antigens; Cell Count; Cell Therapy; Cells; Chronic Lymphocytic Leukemia; Clinical; Clinical Data; Clinical Research; Clinical Trials; Data; Data Set; Disease; Disorder by Site; Economics; Engineering; Engraftment; FDA approved; Future; Generations; Goals; Human; Immune; Immune system; Immunoglobulin Fragments; Immunosuppressive Agents; Immunotherapy; Infusion procedures; Laboratories; Lentivirus Vector; Link; Malignant Neoplasms; Measures; Mediating; Medical; Medicine; Modality; Modeling; Molecular; Mus; Nature; Patients; Peripheral Stem Cell Transplantation; Phase; Phase I Clinical Trials; Procedures; Process; Proteins; Protocols documentation; Radiation therapy; Randomized Clinical Trials; Refractory; Relapse; Reporting; Resistance; Safety; Sampling; Signal Transduction; Site; Specialized Center; Specificity; Stem cell transplant; Stem cells; Surface; System; T cell therapy; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Index; Toxic effect; Transplantation; Tumor Lysis Syndrome; United States National Institutes of Health; Xenograft procedure; autologous lymphocytes; base; cancer therapy; cellular engineering; chemotherapy; chimeric antigen receptor; cost effective; design; experience; extracellular; fludarabine; high risk; in vivo; killings; leukemia; leukemia/lymphoma; meetings; mortality; neoplastic cell; next generation; novel; novel strategies; novel therapeutics; peripheral blood; phase 1 study; pre-clinical; preclinical study; randomized trial; receptor binding; safety testing; standard of care; trafficking; tumor; tumor microenvironment; vector

DESCRIPTION (provided by applicant): There is an unmet medical need for the therapy of leukemia and lymphoma of B cell origin as most adult patients remain incurable. The most potent antitumor effect mediated by the immune system occurs in the setting of allogeneic stem cell transplantation (HSCT). However, most patients are not eligible for this therapy. The objective of this project is to engineer autologous lymphocytes to endow them with the features that would render them equally powerful as allogeneic lymphocytes, and therefore avoid the toxicity and make the therapy routinely available to patients who relapse after initial therapy. Based on recent pilot results in patients with chronic lymphocytic leukemia (CLL), our long term goal is to develop a novel therapy using cell transfer therapy of engineered T cells expressing chimeric antigen receptors (CARs) that bind CD19 for the treatment of B cell malignancies. The key questions currently facing the field are how to: (1) enhance the potency and specificity of autologous T cells so that HSCT can be avoided, and (2) develop mechanisms to increase the persistence of CAR T cells so that they are resistant to the immunosuppressive tumor microenvironment. CARs are an attractive approach to address these issues, because they are off the shelf and HLAindependent. However, in order to establish clinical proof of concept that will be required to justify randomized clinical trials, it will be necessary to optimize vector design, as seemingly small changes in CAR design can have major effects on the antitumor potency of the engineered T cells. Prior preclinical and clinical studies have shown safety of the CAR approach, but efficacy has been disappointing, in part due to poor in vivo survival of CAR expressing cells. Since these early studies utilized CARs containing only a 1st generation single CD3ζ signaling chain, our hypothesis, based on strong pre-clinical data and early phase I clinical results is that our 2nd generation CARs that harbor additional costimulatory domains will augment survival and/or function of CAR-expressing cells in lymphodepleted patients. Our specific aims are to conduct a phase IIa study to: (1) Test the safety, feasibility and tolerability of 3rd generation anti-CD19 CARs in patients with advanced chronic lymphocytic leukemia; 2) Determine the persistence and function of the CAR T cells in patients by measuring the engraftment and trafficking of CAR T cells to the tumor microenvironment, and the duration of B cell aplasia as a proof of mechanism. Other studies will determine safety of the lentiviral vector. Together, these studies will test the central hypothesis that costimulatory signaling domains will provide a selective survival advantage to CAR T cells in patient with CLL, providing proof of mechanism for this new approach. Our approach addresses a clear unmet medical need, as the only curative approach for most patients with relapsed leukemia is HSCT; our CARs could conceivably replace the allogeneic HSCT with an autologous CAR approach, and thereby decrease toxicity and expense associated with transplantation. Finally, the scientific principles evaluated are broadly applicable to other cancer therapies.

描述（由申请人提供）：由于大多数成年患者仍然无法治愈，因此对B细胞源性白血病和淋巴瘤的治疗存在未满足的医疗需求。免疫系统介导的最有效的抗肿瘤作用发生在同种异体干细胞移植（HSCT）中。然而，大多数患者不适合这种治疗。该项目的目标是设计自体淋巴细胞，使其具有与异体淋巴细胞同样强大的特征，从而避免毒性，并使初始治疗后复发的患者能够常规使用该疗法。基于最近在慢性淋巴细胞白血病（CLL）患者中的试点结果，我们的长期目标是开发一种新的治疗方法，使用表达嵌合抗原受体（car）结合CD19的工程化T细胞的细胞转移治疗来治疗B细胞恶性肿瘤。目前该领域面临的关键问题是如何：(1)增强自体T细胞的效力和特异性，从而避免HSCT的发生；(2)开发增强CAR - T细胞持久性的机制，使其能够抵抗免疫抑制的肿瘤微环境。汽车是解决这些问题的一种有吸引力的方法，因为它们是现成的和独立的。然而，为了建立随机临床试验所需的概念临床证明，有必要优化载体设计，因为CAR设计中看似微小的变化可能对工程T细胞的抗肿瘤效力产生重大影响。先前的临床前和临床研究已经证明了CAR方法的安全性，但疗效令人失望，部分原因是CAR表达细胞的体内存活率较差。由于这些早期研究使用的car仅含有第一代单一cd3信号链，基于强有力的临床前数据和早期I期临床结果，我们的假设是，含有额外共刺激结构域的第二代car将增加淋巴衰竭患者中car表达细胞的存活和/或功能。我们的具体目标是开展IIa期研究，以：(1)测试第三代抗cd19 car治疗晚期慢性淋巴细胞白血病患者的安全性、可行性和耐受性；2)通过测量CAR - T细胞在肿瘤微环境中的植入和运输，以及B细胞发育不全的持续时间来确定患者体内CAR - T细胞的持久性和功能，作为其机制的证明。其他研究将确定慢病毒载体的安全性。总之，这些研究将验证中心假设，即共刺激信号域将为CLL患者的CAR - T细胞提供选择性生存优势，为这种新方法的机制提供证据。我们的方法解决了一个明确的未满足的医疗需求，因为大多数复发性白血病患者的唯一治疗方法是HSCT；我们的CAR可以用自体CAR替代同种异体造血干细胞移植，从而降低移植的毒性和费用。最后，所评估的科学原理广泛适用于其他癌症治疗。