CD19 Directed CAR Therapy

描述（由申请人提供）：由于大多数成年患者仍然无法治愈，因此治疗 B 细胞起源的白血病和淋巴瘤的医疗需求尚未得到满足。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）的情况下。然而，大多数患者不适合接受这种治疗。 该项目的目标是对自体淋巴细胞进行工程设计，赋予它们与同种异体淋巴细胞同样强大的功能，从而避免毒性并使初次治疗后复发的患者能够常规使用该疗法。根据最近对慢性淋巴细胞白血病 (CLL) 患者的试点结果，我们的长期目标是开发一种新疗法，使用表达嵌合抗原受体 (CAR) 的工程化 T 细胞进行细胞转移疗法，这些嵌合抗原受体 (CAR) 结合 CD19，用于治疗 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；（2）开发机制来增加CAR T细胞的持久性，使其对免疫抑制性肿瘤微环境具有抵抗力。 CAR 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独立于 HLA。 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 设计中看似微小的变化可能会对工程化 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表明 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 仅包含第一代单 CD3 z 信号链，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 CAR 包含额外的共刺激域，将增强淋巴细胞清除患者中表达 CAR 的细胞的存活和/或功能。我们的具体目标是开展IIa期研究：（1）测试第三代抗CD19 CAR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 细胞在肿瘤微环境中的植入和运输，以及 B 细胞再生障碍的持续时间作为机制证明，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。 这些研究将共同​​检验共刺激信号传导域将为 CLL 患者的 CAR T 细胞提供选择性生存优势的中心假设，为这种新方法提供机制证明。我们的方法解决了一个明显未满足的医疗需求，因为大多数复发性白血病患者的唯一治疗方法是 HSCT；可以想象，我们的 CAR 可以用自体 CAR 方法取代同种异体 HSCT，从而降低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。 公共健康相关性：在该项目中，将针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医疗：患者首先接受 FDA 批准的化疗，然后注入患者 T 淋巴细胞，这些 T 淋巴细胞已在实验室中改变，对肿瘤细胞表面的分子具有重新定向的特异性，这一过程赋予 T 细胞杀死肿瘤细胞的能力。 I 期试验的结果表明，重定向的 T 细胞对患者具有有效的抗肿瘤作用。该项目的研究将进一步确定该手术的安全性和可行性，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.