Chimeric T Cell Antigens Targeting Kappa in B Cell Lymphoma

申请人最近的观察结果表明，遗传修饰的T细胞的过继转移是有效的。 表达B细胞特异性抗体，并将其掺入人工嵌合T细胞受体（CAR）中， 在临床上根除淋巴瘤细胞。这项建议的目的是测试转基因T 表达靶向免疫球蛋白κ-轻链的CAR的细胞可以安全地给予 滤泡性淋巴瘤患者以及这种免疫疗法是否诱导抗肿瘤作用， 损害体液免疫。这一目标将在三个具体的研究目标中得到大力实现。第一、 重要的是在体外和体外验证携带CAR的T细胞的功能并使其最大化。在SCID中， 小鼠模型，并设计出最佳的检测方法，用于评估转基因的持久性和功能性， T细胞输注到淋巴瘤患者体内后。二、实验室检查结果的临床意义 该项目的基础将在I期试验中进行测试，旨在评估安全性，特性和 使用生物学方法，研究了经修饰的T细胞在难治性/复发性淋巴瘤患者中的抗肿瘤活性。 目的1中开发的试验，以评估T细胞功能和持久性。第三，研究计划将 CAR表达T细胞的价值，通过将它们工程化以在免疫后产生靶向CD 22的免疫毒素， 抗CD 19 CAR被抗原接合。如果在小鼠异种移植模型中安全有效， 过继性T细胞免疫疗法的策略利用了两类不同的效应机制， 在未来的临床试验中进行测试，而不是由该奖项资助。在实现这些目标后， 明确抗kappa CAR表达T细胞的输注是否是治疗 人滤泡性淋巴瘤，以及这些细胞在肿瘤处是否可诱导释放免疫毒素 位点将增强抗肿瘤活性。 摘要：滤泡性淋巴瘤不能通过化疗治愈。由于这些肿瘤细胞可以 偶尔会被免疫系统的其他细胞（T淋巴细胞）识别和消除，我们将 基因改变这些T淋巴细胞插入一个人工受体，识别表面的结构 癌性B细胞。当T淋巴细胞接触肿瘤细胞时，它们被激活并杀死肿瘤细胞。 癌这种作用不应显著损害保留免疫力的剩余正常B细胞。

Recent observations by the applicants suggest that adoptive transfer of T cells genetically modified to express a B cell-specific antibody, incorporated into an artificial chimeric T-cell receptor (CAR), might eradicate lymphoma cells in a clinical setting. The intent of this proposal is to test whether transgenic T cells that express CAR targeted to the kappa-light chain of immunoglobulin can be safely administered to patients with follicular lymphoma and whether such immunotherapy induces antitumor effects without impairing humoral immunity. This objective will be vigorously pursued in three specific research aims. First, it will be important to validate and maximize the function of CAR-bearing T cells both in vitro and. in a SCID mouse model and to devise optimal assaysfor evaluating the persistence and functionality of the transgenic T cells after their infusion into lymphoma patients. Second, the clinical significance of the laboratory findings underlying this project will be tested in a Phase I trial designed to evaluatethe safety, properties and antitumor activity of the modified T cells in patients with refractory/relapsed lymphoma, using the biological assays developedin Aim 1to assessT-cell function and persistence. Third, studies are planned to extend the value of the CAR-expressing T cells by engineering them to produce a CD22-targeted immunotoxin after the anti-CD19 CAR is engaged by antigen. If safe and effective in a murine xenograft model, this combined strategy of adoptive T cell immunotherapy, which exploits two distinct classes of effector mechanisms, will undergo testing in future clinical trials not funded by this award. Upon completion of these aims, it should be clear whether the infusion of anti-kappa CAR-expressingT cells is a legitimate approach to the treatment of human follicular lymphoma, and whether the inducible release of immunotoxin by these cells at the tumor site will enhance antitumor activity. Lay Abstract: Follicular lymphoma cannot be cured by chemotherapy.Since these tumor cells can occasionally be recognized and eliminated by other cells of the immune system (T lymphocytes) we will genetically alter these T lymphocytesinserting an artificial receptor that recognizes a structure on the surface of the cancerous B cells. When the T lymphocytes contact the tumor cells, they become activated and kill the cancer. This effect should not significantly damage the remaining normal B-cells preserving the immunity.