肿瘤细胞治疗研究
英文原题：Fine-tuning affinity and spacer design enhances T cell potency in DLL3 and BCMA CAR T cells.
本研究强调了CAR设计在增强T细胞功能中的关键作用，表明高亲和力CAR联合中等长度间隔区在靶向BCMA和DLL3抗原时表现出更优的性能。
嵌合抗原受体（CAR）修饰的 T 细胞因其临床成功而受到广泛关注，最终促成六种获 FDA 批准的血液系统恶性肿瘤疗法。值得注意的是，靶向 CD19 的 CAR T 细胞疗法在治疗 B 细胞恶性肿瘤方面取得了显著临床疗效，但这些深度且持久的缓解并未在针对其他适应证的 CAR T 疗法中观察到，尤其是实体瘤。CAR 构建体的关键设计要素——即抗原结合亲和力和间隔区长度——在决定 T 细胞效应功能和整体治疗效果中发挥关键作用。优化 CAR 设计可能增强 T 细胞功能，扩展临床应用，并有可能将 CAR T 细胞疗法应用于更广泛的恶性肿瘤。在本研究中，针对 BCMA 和 DLL3 肿瘤抗原的亲和力变体与间隔区变体 CAR 通过体外测量抗原结合特性和效应功能进行评估。每一组 CAR 的抗原结合亲和力跨越 2-3 个对数级（BCMA：181 pM KD 至 74 nM KD，DLL3：417 pM 至 407 nM）。此外，用由 BCMA + H929 和 DLL3 + SHP77 肿瘤细胞组成的肿瘤球攻击 CAR T 细胞。我们表明，对于两种肿瘤模型，较高亲和力 CAR（KD 强于约 100 nM）与中等长度间隔区（IgG1 Fc，CH2-CH3，230AA）配对，引发了最强水平的肿瘤杀伤、CAR + T 细胞扩增和促炎细胞因子产生。这些 CAR 在偶联试验中测量时显示出最强的细胞亲和力，提示细胞亲和力与 T 细胞功能表现之间存在关系。本研究强调了 CAR 设计在增强 T 细胞功能中的关键作用，证明高亲和力 CAR 与中等长度 spacer 组合在靶向 BCMA 和 DLL3 抗原时表现出更优性能。本研究为理性 CAR 设计提供了框架，为将 CAR T 细胞疗法的临床用途拓展至血液系统恶性肿瘤之外提供了策略依据。
Chimeric antigen receptor (CAR)-modified T cells have garnered substantial attention due to their clinical success, culminating in six Food and Drug Administration-approved therapies for hematological malignancies. Notably, CD19-specific CAR T cell therapies have achieved remarkable clinical efficacy in treating B-cell malignancies, but these profound and durable responses are not observed in CAR T therapies targeting other indications, particularly solid tumors. Key design elements of CAR constructs - namely, antigen binding affinity and spacer length - play critical roles in determining T cell effector function and overall therapeutic effectiveness. Refining CAR designs may enhance T cell functionality, extend clinical application, and potentially apply CAR T cell therapies across a wider array of malignancies. In this study, affinity variant and spacer variant CARs targeting BCMA and DLL3 tumor antigens were evaluated using in vitro measurements of antigen-binding properties and effector function. Each panel of CARs spanned 2-3 logs of antigen binding affinity (BCMA: 181 pM KD to 74 nM KD, DLL3: 417 pM to 407 nM). Additionally, CAR T cells were challenged with tumor spheroids composed of BCMA + H929 and DLL3 + SHP77 tumor cells. We show that for both tumor models, higher affinity CARs (KD stronger than approximately 100 nM) paired with an intermediate length spacer (IgG1 Fc, CH2-CH3, 230AA) elicited the strongest levels of tumor killing, CAR + T cell expansion, and proinflammatory cytokine production. These CARs displayed the strongest cellular affinity when measured in a conjugation assay, suggesting a relationship between cellular affinity and T cell functional performance. This study highlights the critical role of CAR design in enhancing T cell functionality, demonstrating that high-affinity CARs combined with intermediate-length spacers yield superior performance in targeting BCMA and DLL3 antigens. This study provides a framework for rational CAR design, informing strategies to broaden the clinical utility of CAR T-cell therapies beyond hematologic cancers.
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