文章：

一种新型同种异体利妥昔单抗偶联γδT细胞疗法用于治疗复发/难治性B细胞淋巴瘤

A Novel Allogeneic Rituximab-Conjugated Gamma Delta T Cell Therapy for the Treatment of Relapsed/Refractory B-Cell Lymphoma

原文发布日期：4 October 2023

DOI: 10.3390/cancers15194844

类型: Article

开放获取: 是

英文摘要：

Chimeric antigen receptor T cell (CAR-T) therapy has been applied in the treatment of B-cell lymphoma; however, CAR-T manufacturing requires virus- or non-virus-based genetic modification, which causes high manufacturing costs and potential safety concerns. Antibody–cell conjugation (ACC) technology, which originated from bio-orthogonal click chemistry, provides an efficient approach for arming immune cells with cancer-targeting antibodies without genetic modification. Here, we applied ACC technology in Vγ9Vδ2 T (γδ2 T) cells to generate a novel off-the-shelf CD20-targeting cell therapy ACE1831 (rituximab-conjugated γδ2 T cells) against relapsed/refractory B-cell lymphoma. ACE1831 exhibited superior cytotoxicity against B-cell lymphoma cells and rituximab-resistant cells compared to γδ2 T cells without rituximab conjugation. The in vivo xenograft study demonstrated that ACE1831 treatment strongly suppressed the aggressive proliferation of B-cell lymphoma and prolonged the survival of tumor-bearing mice with no observed toxicity. Mass spectrometry analysis indicated that cell activation receptors including the TCR complex, integrins and cytokine receptors were conjugated with rituximab. Intriguingly, the antigen recognition of the ACC-linked antibody/receptor complex stimulated NFAT activation and contributed to ACE1831-mediated cytotoxicity against CD20-expressing cancer cells. This study elucidates the role of the ACC-linked antibody/receptor complex in cytotoxicity and supports the potential of ACE1831 as an off-the-shelf γδ2 cell therapy against relapsed/refractory B-cell lymphoma.

摘要翻译： 

嵌合抗原受体T细胞疗法已应用于B细胞淋巴瘤的治疗，但该疗法需通过病毒或非病毒载体进行基因修饰，导致生产成本高昂且存在潜在安全隐患。基于生物正交点击化学发展而来的抗体-细胞偶联技术，为免疫细胞装载靶向抗体提供了一种无需基因修饰的高效策略。本研究将该技术应用于Vγ9Vδ2 T细胞，成功构建了靶向CD20的新型现货型细胞疗法ACE1831（利妥昔单抗偶联γδ2 T细胞），用于治疗复发/难治性B细胞淋巴瘤。相较于未偶联利妥昔单抗的γδ2 T细胞，ACE1831对B细胞淋巴瘤细胞及利妥昔单抗耐药细胞展现出更强的细胞毒性。体内异种移植实验表明，ACE1831能显著抑制B细胞淋巴瘤的侵袭性增殖，延长荷瘤小鼠生存期且未观察到毒性反应。质谱分析显示，包括TCR复合体、整合素及细胞因子受体在内的细胞活化受体均与利妥昔单抗成功偶联。值得注意的是，ACC偶联抗体/受体复合物的抗原识别可激活NFAT信号通路，进而增强ACE1831对CD20阳性癌细胞的杀伤作用。本研究阐明了ACC偶联抗体/受体复合物在细胞毒性中的作用机制，为ACE1831作为治疗复发/难治性B细胞淋巴瘤的现货型γδ2细胞疗法提供了理论依据。

原文链接：

A Novel Allogeneic Rituximab-Conjugated Gamma Delta T Cell Therapy for the Treatment of Relapsed/Refractory B-Cell Lymphoma