CD19 Directed CAR Therapy

描述(申请人提供)：由于大多数成人患者仍然无法治愈，治疗白血病和B细胞淋巴瘤的医学需求尚未得到满足。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，大多数患者不符合这种疗法的条件。该项目的目标是改造自体淋巴细胞，使其具有与同种异体淋巴细胞一样强大的功能，从而避免毒性，并使最初治疗后复发的患者常规使用该疗法。基于最近在慢性淋巴细胞白血病(CLL)患者中的试验结果，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(CARS)的工程T细胞的细胞转移疗法来治疗B细胞恶性肿瘤。目前该领域面临的关键问题是如何：(1)提高自体T细胞的效力和特异性，以避免HSCT；(2)开发机制，增加CAR T细胞的持久性，使其对免疫抑制的肿瘤微环境具有抵抗力。汽车是解决这些问题的一个有吸引力的方法，因为它们是现成的，而且不依赖于硬件。然而，为了建立随机临床试验所需的临床概念证明，有必要优化载体设计，因为CAR设计中看似很小的变化可能会对工程T细胞的抗肿瘤效力产生重大影响。以前的临床前和临床研究已经表明CAR方法是安全的，但疗效一直令人失望，部分原因是CAR表达细胞在体内的存活率很低。由于这些早期研究使用的CARS只包含第一代单一CD3信号链，我们的假设是，基于强大的临床前数据和早期I期临床结果，我们的第二代CARS包含额外的共刺激结构域，将增强淋巴枯竭患者CAR表达细胞的存活率和/或功能。我们的具体目标是进行IIa期研究，以：(1)测试第三代抗CD19 CARS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)通过检测CAR T细胞在肿瘤微环境中的植入和运输以及B细胞再生障碍性贫血的持续时间来确定CAR T细胞在患者体内的持久性和功能。其他研究将确定慢病毒载体的安全性。总之，这些研究将检验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的中心假设，为这一新方法的机制提供证据。我们的方法解决了一个明显的未得到满足的医疗需求，因为大多数复发白血病患者的唯一治疗方法是造血干细胞移植；我们的CARS可以用自体CAR方法取代同种异体造血干细胞移植，从而减少与移植相关的毒性和费用。最后，评估的科学原理广泛适用于其他癌症疗法。 与公共卫生相关：在这个项目中，一种使用定制免疫系统的个性化药物将被测试用于晚期慢性淋巴细胞白血病患者：患者首先接受FDA批准的化疗，然后给患者T淋巴细胞输注，这些T淋巴细胞在实验室中被改变为具有肿瘤细胞表面分子的重定向特异性，这一过程使T细胞具有杀死肿瘤细胞的能力。中试I期试验的结果表明，重定向的T细胞在患者中具有强大的抗肿瘤作用。该项目的研究将进一步确定该方法的安全性和可行性，并将为这一有希望的新疗法在晚期慢性淋巴细胞白血病患者的IIa期临床试验中的作用机制提供必要的信息。

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.