Allogeneic BAFF Ligand Based CAR T Cells as a Novel Therapy for B Cell Malignancies

摘要 自2017年FDA首次批准嵌合抗原受体（CAR）T细胞治疗以来，使用工程化T细胞治疗已经成为一项新的研究。 表达特异性汽车以治疗癌症的细胞已经为许多患者产生了持久的治愈。然而，A B细胞恶性肿瘤患者的显著亚群在治疗后由于缺乏CAR T细胞而复发 持续性和癌细胞随时间变化并逃避治疗干预的能力。自体 T细胞疗法还带来了巨大的时间轴和成本负担，使得广泛采用变得困难。在这 应用中，我们提出了一种新的同种异体CAR T细胞疗法，旨在改善患者的预后， 套细胞淋巴瘤（MCL），通过克服目前存在的缺陷，CD 19靶向 治疗学B细胞活化因子（BAFF）为正常和肿瘤性B细胞提供关键的存活信号 细胞通过受体家族（BAFF受体、TACI和BCMA），从而减轻抗原逃逸的可能性。 BAFF及其受体在B细胞恶性肿瘤的背景下仍未得到充分研究， 已经压倒性地依赖于泛B细胞抗原如CD 19和CD 20。由于BAFF结合其受体 我们相信，适度的亲和力会增加这些细胞形成记忆群体的能力， 参与连环杀人我们将在同种异体γ δ T细胞中利用这种基于配体的CAR设计， 由于γδ T细胞已被证明在体外具有高复制特性，并且不介导移植物 新宿主的抗宿主病我们已经产生了初步的数据，证实我们有能力使用非- 病毒TcBuster DNA转座子系统产生具有BAFF-CAR表达的T细胞。的总体目标 该提案旨在进一步开发和评估我们的γδ BAFF-CAR T细胞疗法用于治疗IND中的MCL 赋能研究。在这样做的过程中，我们的同种异体BAFF-CAR T细胞疗法支持了急需的转变， 针对新的肿瘤抗原的治疗开发，所述新的肿瘤抗原防止抗原逃逸，同时减少肿瘤细胞的增殖。 通过使用容易获得的细胞来源，减少了与细胞疗法相关的制造负担。

ABSTRACT Since the first FDA approval of chimeric antigen receptor (CAR) T cell therapy in 2017, the use of engineered T cells expressing specific CARs to treat cancer has generated durable cures for many patients. Nevertheless, a significant subset of patients with B cell malignancies relapse following treatment due to lack of CAR T cell persistence and the ability of cancer cells to change with time and evade therapeutic interventions. Autologous T cell therapies also carry significant timeline and cost burdens, making widespread adoption difficult. In this application, we propose a novel allogeneic CAR T cell therapy aimed at improving outcomes for patients with mantle cell lymphoma (MCL) by overcoming deficiencies present in current generation CD19 targeted therapeutics. B cell activating factor (BAFF) provides critical survival signals to both normal and neoplastic B cells through a family of receptors (BAFF receptor, TACI, and BCMA) thus mitigating potential for antigen escape. BAFF and its receptors have remained underexplored in the context of B cell malignancies where strategies have relied overwhelmingly on pan B cell antigens such as CD19 and CD20. Since BAFF binds its receptors with moderate affinity, we believe this will increase the ability of these cells to form memory populations and engage in serial killing. We will leverage this ligand-based CAR design in an allogeneic gamma delta (γδ) T cell platform, as γδ T cells have been shown to have high replicative properties in vitro and do not mediate graft versus host disease in new hosts. We have produced preliminary data that confirms our ability to use the non- viral TcBuster DNA transposon system to generate T cells with BAFF-CAR expression. The overall objective of this proposal is to further develop and evaluate our γδ BAFF-CAR T cell therapy for the treatment of MCL in IND enabling studies. In doing so, our allogeneic BAFF-CAR T cell therapy supports an urgently needed shift in therapeutic development toward new tumor antigens that protect against antigen escape while reducing the manufacturing burden associated with cellular therapies through use of a readily available cell source.