肿瘤细胞治疗研究
英文原题：Functional differences between CLL- and ALL-derived CAR T cells in a 3D tumor microenvironment highlight CXCR4 and IL-10 as potential modulatory targets.
尽管靶向治疗取得了进展，慢性淋巴细胞白血病（CLL）的治疗仍然具有挑战性，凸显了对有效新治疗策略的迫切需求。
尽管靶向治疗取得了进展，慢性淋巴细胞白血病（CLL）的治疗仍然具有挑战性，凸显了对有效新治疗策略的迫切需求。虽然嵌合抗原受体（CAR）T细胞疗法显著改善了急性淋巴细胞白血病（ALL）的结局，但其在CLL中的疗效有限。我们假设这种差异源于CLL中显著的CAR T细胞耗竭和免疫抑制性肿瘤微环境（TME）。我们利用自体3D TME共培养模型，在生理相关条件下研究了来源于CLL和ALL患者的CAR T细胞的功能。我们的结果显示，与ALL患者相比，CLL患者的CAR T细胞耗竭水平增加且细胞毒性降低。重要的是，将CAR T细胞治疗与白细胞介素-10（IL-10）或CXCR4阻断联合使用，有效提高了对CLL细胞的细胞毒性，即使在3D模型中被基质保护的区域也是如此。这些发现为CLL中CAR T细胞功能障碍提供了见解，并支持新的TME靶向联合策略以改善临床结局。
Despite advances in targeted therapies, treatment of chronic lymphocytic leukemia (CLL) remains challenging, highlighting the urgent need for effective new therapeutic strategies. Although chimeric antigen receptor (CAR) T-cell therapy dramatically improved outcomes in acute lymphoblastic leukemia (ALL), its efficacy in CLL is limited. We hypothesize that this disparity results from pronounced CAR T-cell exhaustion and the immunosuppressive tumor microenvironment (TME) in CLL. We utilized an autologous 3D TME co-culture model to investigate the functionality of CAR T cells derived from CLL and ALL patients within physiologically relevant conditions. Our results revealed increased exhaustion levels and diminished cytotoxicity of CAR T cells from CLL patients compared to those from ALL patients. Importantly, combining CAR T-cell treatment with interleukin-10 (IL-10) or CXCR4 blockade effectively improved cytotoxicity against CLL cells, even in stromal-protected regions within the 3D model. These findings offer insights into CAR T-cell dysfunction in CLL and support novel TME-targeted combination strategies to improve clinical outcomes.
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