CD19 Directed CAR Therapy

描述（由申请方提供）：由于大多数成人患者仍然无法治愈，因此治疗B细胞来源的白血病和淋巴瘤的医疗需求尚未得到满足。由免疫系统介导的最有效的抗肿瘤作用发生在异基因干细胞移植（HSCT）的环境中。然而，大多数患者不适合这种治疗。 该项目的目的是设计自体淋巴细胞，使其具有与同种异体淋巴细胞同样强大的功能，从而避免毒性，并使治疗常规用于初始治疗后复发的患者。基于慢性淋巴细胞白血病（CLL）患者的近期试验结果，我们的长期目标是开发一种新型疗法，该疗法使用表达嵌合抗原受体（CAR）的工程化T细胞的细胞转移疗法，用于治疗B细胞恶性肿瘤，嵌合抗原受体（CAR）结合CD 19。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，以避免HSCT，以及（2）开发增加CAR T细胞持久性的机制，使其对免疫抑制性肿瘤微环境具有抗性。 汽车是解决这些问题的一种有吸引力的方法，因为它们是现成的并且不依赖于HLA。 然而，为了建立证明随机临床试验合理性所需的临床概念证明，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化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显示了CAR方法的安全性，但功效令人失望，部分原因是CAR表达细胞的体内存活率差。由于这些早期研究利用仅含有第一代单CD 3信号传导链的汽车，因此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，我们的第二代汽车具有额外的共刺激结构域，将增加淋巴细胞耗竭患者中CAR表达细胞的存活和/或功能。我们的具体目标是进行IIa期研究：（1）测试第三代抗CD 19汽车在晚期慢性淋巴细胞白血病患者中的安全性，可行性和耐受性; 2）通过测量CAR T细胞向肿瘤微环境的植入和运输来确定患者中CAR T细胞的持久性和功能，和B细胞再生障碍的持续时间作为机制的证据。其他研究将确定慢病毒载体的安全性。 总之，这些研究将测试中心假设，即共刺激信号结构域将为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;我们的汽车可以用自体CAR方法替代同种异体HSCT，从而降低与移植相关的毒性和费用。最后，所评估的科学原理广泛适用于其他癌症治疗。 公共卫生相关性：在该项目中，将对晚期慢性淋巴细胞白血病患者测试一种使用定制免疫系统的个性化药物：患者首先用FDA批准的化疗进行治疗，然后输注在实验室中已经改变的患者T淋巴细胞以具有对肿瘤细胞表面上的分子的重定向特异性，这一过程赋予T细胞杀死肿瘤细胞的能力。初步I期试验的结果表明，重定向的T细胞在患者中具有强效的抗肿瘤作用。该项目的研究将进一步确定该程序的安全性和可行性，并将在晚期慢性淋巴细胞白血病患者的IIa期临床试验中提供有关这种有前途的新疗法的作用机制的重要信息。

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. PUBLIC HEALTH RELEVANCE: In this project a form of personalized medicine using a customized immune system will be tested for patients with advanced chronic lymphocytic leukemia: the patient is first treated with FDA approved chemotherapy and then infused with patient T lymphocytes that have been altered in the laboratory to have redirected specificity for a molecule on the surface of the tumor cells, a process that endows the T cells with the capability to kill tumor cells. The results in a pilot phase I trial indicate that the redirected T cells have potent antitumor effects in patients. The studies in this project will establish further the safety and feasibility of the procedure, and will provide essential information on the mechanism of action of this promising new therapy in a phase IIa clinical trial in patients with advanced chronic lymphocytic leukemia.