Chimeric T Cell Antigens Targeting Kappa in B Cell Lymphoma

申请人最近的观察表明，通过将转基因T细胞转移到 表达B细胞特异性抗体，结合到人工嵌合T细胞受体(CAR)中，可能会 在临床环境中根除淋巴瘤细胞。这项建议的目的是测试转基因T细胞 表达针对免疫球蛋白kappa轻链的CAR的细胞可以安全地注射到 滤泡性淋巴瘤患者以及这种免疫疗法是否在没有 体液免疫受损。这一目标将在三个具体的研究目标中积极实现。第一, 在体外和体外，验证和最大限度地发挥车载T细胞的功能将是重要的。在SCID中 小鼠模型，并设计最佳的分析方法来评估转基因的持久性和功能性。 T细胞输注后进入淋巴瘤患者体内。二、实验室检查结果的临床意义 该项目的基础将在第一阶段试验中进行测试，旨在评估安全、性能和 应用生物学方法研究修饰T细胞在难治/复发淋巴瘤患者中的抗肿瘤活性 目的1评估T细胞的功能和持久性。第三，计划扩大研究范围 表达CAR的T细胞通过基因工程产生CD22靶向免疫毒素的价值 抗CD19抗体与抗原结合。如果在小鼠异种移植模型中安全有效，这种联合 过继T细胞免疫治疗策略，利用两种不同的效应机制，将 在不受该奖项资助的未来临床试验中进行测试。在完成这些目标之后，它应该是 明确输注表达kappa Car的抗T细胞是否是治疗慢性粒细胞白血病的合法方法 人类滤泡性淋巴瘤，以及这些细胞在肿瘤处诱导免疫毒素的释放 该网站将增强抗肿瘤活性。 滤泡性淋巴瘤不能通过化疗治愈，因为这些肿瘤细胞可以 偶尔会被免疫系统的其他细胞(T淋巴细胞)识别和消除 从基因上改变这些T淋巴细胞，植入一种人工受体，识别表面的结构 癌变的B细胞。当T淋巴细胞接触肿瘤细胞时，它们被激活并杀死 癌症。这种影响应该不会对保持免疫的剩余正常B细胞造成显著损害。

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.