肿瘤细胞治疗研究
英文原题：TIM3-targeted delivery of venetoclax overcomes drug resistance and reinvigorates NK cell activity in acute myeloid leukemia.
急性髓系白血病（AML）仍然具有挑战性，尤其是对于对基于维奈克拉（VEN）的方案产生耐药性的老年或不适合强化疗的个体。
急性髓系白血病（AML）仍然具有挑战性，尤其是对于对基于venetoclax（VEN）的方案产生耐药性的老年或不适合强化疗的个体。尽管TIM3是一个有前景的AML靶点，但临床阻断效果欠佳。在此，我们开发了VINCENT（靶向TIM3的VEN整合NK 细胞衔接器），这是一种将抗CD16和抗TIM3抗体与纳米制剂VEN相结合的治疗平台。在VEN耐药的AML细胞系和患者来源的异种移植模型中，VINCENT通过增强VEN递送、消除TIM3+原始细胞和功能失调的T细胞并激活自然杀伤（NK）细胞来克服耐药性。在原代AML样本中，VINCENT选择性杀伤耐药原始细胞，其疗效与NK细胞与TIM3+原始细胞的比值相关。单细胞转录组学显示，VINCENT清除高TIM3原始细胞，并将免疫抑制微环境重塑为免疫活性状态。总体而言，VINCENT同时解决VEN耐药、NK细胞功能障碍和免疫逃逸，为标准化VEN方案治疗失败的老年或不适合的AML个体提供了一种个性化选择。
Acute myeloid leukemia (AML) remains challenging, especially for older or unfit individuals who develop resistance to venetoclax (VEN)-based regimens. Although TIM3 represents a promising AML target, clinical blockade has yielded suboptimal outcomes. Here, we develop VINCENT (VEN-integrated natural killer cell engager targeting TIM3), a therapeutic platform combining anti-CD16 and anti-TIM3 antibodies with nanoformulated VEN. In VEN-resistant AML cell lines and patient-derived xenograft models, VINCENT overcomes resistance by enhancing VEN delivery, eliminating TIM3 + blasts and dysfunctional T cells and activating natural killer (NK) cells. In primary AML samples, VINCENT selectively kills drug-resistant blasts, with efficacy correlating with the NK cell-to-TIM3 + blast ratio. Single-cell transcriptomics reveals VINCENT depletes high-TIM3 blasts and remodels the immunosuppressive microenvironment toward immune competence. Collectively, VINCENT simultaneously addresses VEN resistance, NK cell dysfunction and immune evasion, offering a personalized option for elderly or unfit individuals with AML failing standard VEN regimens.
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