肿瘤细胞治疗研究
英文原题：A Novel Allogeneic Rituximab-Conjugated Gamma Delta T Cell Therapy for the Treatment of Relapsed/Refractory B-Cell Lymphoma.
CAR-T 细胞疗法已应用于 B 细胞淋巴瘤的治疗；然而，CAR-T 制备需要基于病毒或非病毒的基因修饰，这导致高昂的生产成本和潜在的安全性担忧。
CAR-T 细胞已用于治疗B细胞淋巴瘤，但其制备需要采用病毒或非病毒基因修饰，导致生产成本高并带来潜在安全性顾虑。抗体-细胞偶联（ACC）技术源自生物正交点击化学，可在不进行基因修饰的情况下，以靶向癌症的抗体赋能免疫细胞。本研究将ACC技术应用于Vγ9Vδ2 T（γδ T）细胞，开发一种现货型CD20靶向细胞疗法ACE1831（利妥昔单抗偶联γδ T细胞），用于治疗复发或难治性B细胞淋巴瘤。与未偶联利妥昔单抗的γδ T细胞相比，ACE1831对B细胞淋巴瘤细胞和利妥昔单抗耐药细胞具有更强细胞毒性。体内异种移植研究显示，ACE1831可强效抑制侵袭性B细胞淋巴瘤增殖，并延长荷瘤小鼠生存期，且未观察到毒性。质谱分析显示，包括TCR复合物、整合素和细胞因子受体在内的细胞活化受体与利妥昔单抗发生偶联。值得注意的是，ACC连接的抗体/受体复合物识别抗原后可激活NFAT，并促进ACE1831对CD20表达癌细胞的细胞毒作用。本研究阐明了ACC连接的抗体/受体复合物在细胞毒作用中的功能，并支持ACE1831作为复发或难治性B细胞淋巴瘤现货型γδ T细胞疗法的潜力。
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 V 9V 2 T ( 2 T) cells to generate a novel off-the-shelf CD20-targeting cell therapy ACE1831 (rituximab-conjugated 2 T cells) against relapsed/refractory B-cell lymphoma. ACE1831 exhibited superior cytotoxicity against B-cell lymphoma cells and rituximab-resistant cells compared to 2 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 2 cell therapy against relapsed/refractory B-cell lymphoma.
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