PO.IM01.06 · 免疫学
CD19-CAR T细胞制造过程中的环境调控在皮下NALM6肿瘤模型中影响抗肿瘤效力
Environmental conditioning during CD19-CAR T cell manufacturing impacts antitumor potency in a subcutaneous NALM6 tumor model
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
嵌合抗原受体(CAR)T细胞疗法已彻底改变了血液系统恶性肿瘤的治疗结局，但优化制造条件对于提高效力和一致性仍然至关重要。我们此前证实，在生理氧浓度和加压条件下培养CAR-T细胞可改善其在弥散性NALM6人类ALL模型中的持久性和疗效。在本研究中，我们探讨了这些优化的制造条件是否同样能改善皮下NALM6异种移植模型中的抗肿瘤活性。CD19靶向CAR-T细胞在三种条件下扩增：标准CO2培养(21% O2 + 0 PSI)、伴高压的轻度低氧(15% O2 + 5 PSI，模拟动脉血和外周血环境)，以及伴高压的低氧(5% O2 + 5 PSI，模拟实体瘤和骨髓微环境)。在10天的肿瘤生长期后，2.5e6个CAR+ T细胞的剂量在所有条件下均于T细胞给药后20天实现肿瘤完全清除，其中5% O2 + 5 PSI条件下肿瘤消退更快(T细胞给药后7天)，相比常氧或轻度低氧条件(T细胞给药后10天)。这些体内结果与增强的体外功能活性一致，表现为在低于1:30的CAR-T与效应靶比下具有更强的细胞毒性以及更高的细胞因子生成。这种一致性与我们此前在弥散性模型中的发现相呼应，即在生理相关条件下培养的CAR-T细胞表现出可预测体内疗效的体外特征。初步结果显示，5% O2 + 5 PSI条件下具有增强的效力和持久性。为确定这些制造优势是否在更低CAR-T剂量下得以维持，一项剂量滴定研究正在进行中，完整结果即将公布。这些数据凸显了使用GMP AVATAR Foundry进行生理性制造以增强CAR-T功能并降低有效剂量的潜力，支持可扩展的下一代细胞疗法。
查看英文原文 English abstract
Chimeric Antigen Receptor (CAR) T cell therapy has transformed outcomes for hematologic malignancies, yet optimizing manufacturing conditions remains critical to improving potency and consistency. We previously demonstrated that culturing CAR-T cells under physiological oxygen and pressurized conditions improved persistence and efficacy in a disseminated NALM6 human ALL model.In this study, we investigated whether these optimized manufacturing conditions similarly improve antitumor activity in a subcutaneous NALM6 xenograft model. CD19-targeted CAR-T cells were expanded under three conditions: standard CO 2 incubation (21% O 2 + 0 PSI), mild hypoxia with hyperbaric pressure (15% O 2 + 5 PSI), reflecting arterial and peripheral blood environments, and hypoxia with hyperbaric pressure (5% O 2 + 5 PSI), modeling the solid tumor and bone marrow microenvironments. After a 10-day tumor stage, a dose of 2.5e6 CAR+ T cells achieved complete tumor clearance in all conditions at 20 days post T cell dose, with faster tumor regression under 5% O 2 + 5 PSI conditions (7 days post T cell dose) compared to normoxia or mild hypoxia (10 days post T cell dose). These in vivo outcomes were consistent with enhanced in vitro functional activity, characterized by greater cytoxicity at CAR-T-to-effector ratios under 1:30 and increased cytokine production. This consistency mirrors our previous findings in the disseminated model, where CAR-T cells cultured under physiologically relevant conditions demonstrated the in vitro characteristics predictive of in vivo efficacy. Preliminary findings show enhanced potency and persistence under 5% O 2 + 5 PSI conditions. To determine whether these manufacturing advantages are sustained at lower CAR-T doses, a dose titration study is currently in progress, with complete results forthcoming.These data highlight the potential of physiological manufacturing with the GMP AVATAR Foundry to enhance CAR-T function and lower effective doses, supporting scalable next-generation cell therapies.
利益披露 Disclosure
C. Garcia, None..
A. Czachorowski, None..
L. Kucharczyk, None..
N. Czeryba, None..
A. Hodgins-Davis, None..
T. Sullivan, None..
Y. Bronevetsky, None.