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细胞疗法以来，工程化T细胞的使用 表达特定CAR治疗癌症的细胞已经为许多患者创造了持久的治愈方法。尽管如此，一个 因CAR T细胞缺乏而经治疗后复发的B细胞恶性肿瘤患者中的显著亚群 癌细胞的持久性和随时间变化并逃避治疗干预的能力。自体 T细胞疗法也带来了巨大的时间表和成本负担，使得广泛采用变得困难。在这 应用，我们提出了一种新的同种异体CAR T细胞疗法，旨在改善慢性粒细胞白血病患者的预后 克服当代靶向CD19缺陷的套细胞淋巴瘤(MCL) 治疗学。B细胞激活因子(BAFF)为正常和肿瘤B细胞提供关键的生存信号 细胞通过一系列受体(BAFF受体、TACI和BCMA)，从而减少抗原逃逸的可能性。 在B细胞恶性肿瘤的背景下，BAFF及其受体仍未得到充分研究 绝大多数依赖于CD19和CD20等泛B细胞抗原。因为BAFF结合了它的受体 我们相信，通过适度的亲和力，这将增加这些细胞形成记忆群体的能力，并 参与连环杀戮。我们将在异基因伽马三角洲(γδ)T细胞中利用这种基于配体的汽车设计 平台，因为γδT细胞已被证明在体外具有高复制特性，并且不介导移植 与新宿主中的宿主疾病相比较。我们已经产生了初步数据，证实了我们有能力使用非 病毒TcBuster DNA转座子系统产生表达BAFF-CAR的T细胞。总的目标是 这项建议是为了进一步开发和评估我们的γδBAFF-CAR T细胞疗法治疗IND中的MCL 使研究成为可能。通过这样做，我们的同种异体BAFF-CAR T细胞疗法支持了一种迫切需要的转变 新的肿瘤抗原的治疗进展，防止抗原逃逸，同时减少 通过使用容易获得的细胞源来制造与细胞疗法相关的负担。

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.