美国国立卫生研究院Rosandra N. Kaplan等研究人员合作揭示，接受GD2 CAR-T细胞疗法的实体瘤患者CAR-T细胞扩增的免疫决定因素。相关论文于2023年12月21日在线发表在《癌细胞》杂志上。

研究人员对GD2嵌合抗原受体 T 细胞（CAR-T）（GD2-CAR.OX40.28.z.iC9）进行了I期试验（NCT02107963），证明了在患有骨肉瘤和神经母细胞瘤的儿童和年轻成人中用药的可行性和安全性。由于CAR-T疗效需要充分的CAR-T扩增，因此不同剂量水平的患者被分为扩增效果好和效果差两组。通过多维蛋白质组、转录组和表观遗传学分析，研究人员对患者样本进行了评估。T细胞评估确定了与良好扩增相关的治疗前分离中的幼稚T细胞，以及扩增不良的CAR-T产品中的衰竭T细胞。

髓系细胞评估发现，治疗前血液净化中的CXCR3⁺单核细胞具有良好的扩增能力。对治疗后样本的纵向分析发现，随着CAR-T数量的减少，所有组别中的CXCR3^-经典单核细胞都有所增加。总之，这些数据揭示了CAR-T生物学的介导分子和扩增的相关性，可用于推进实体瘤患者的免疫疗法。

研究人员表示，CAR-T对血液肿瘤有显著疗效，但对实体瘤的反应有限。

附：英文原文

Title: Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy

Author: Sabina Kaczanowska, Tara Murty, Ahmad Alimadadi, Cristina F. Contreras, Caroline Duault, Priyanka B. Subrahmanyam, Warren Reynolds, Norma A. Gutierrez, Reema Baskar, Catherine J. Wu, Franziska Michor, Jennifer Altreuter, Yang Liu, Aashna Jhaveri, Vandon Duong, Hima Anbunathan, Claire Ong, Hua Zhang, Radim Moravec, Joyce Yu, Roshni Biswas, Stephen Van Nostrand, James Lindsay, Mina Pichavant, Elena Sotillo, Donna Bernstein, Amanda Carbonell, Joanne Derdak, Jacquelyn Klicka-Skeels, Julia E. Segal, Eva Dombi, Stephanie A. Harmon, Baris Turkbey, Bita Sahaf, Sean Bendall, Holden Maecker, Steven L. Highfill, David Stroncek, John Glod, Melinda Merchant, Catherine C. Hedrick, Crystal L. Mackall, Sneha Ramakrishna, Rosandra N. Kaplan

Issue&Volume: 2023-12-21

Abstract: Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors,but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963)of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administrationin children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacyrequires adequate CAR-T expansion, patients were grouped into good or poor expandersacross dose levels. Patient samples were evaluated by multi-dimensional proteomic,transcriptomic, and epigenetic analyses. T cell assessments identified naive T cellsin pre-treatment apheresis associated with good expansion, and exhausted T cells inCAR-T products with poor expansion. Myeloid cell assessment identified CXCR3+ monocytes in pre-treatment apheresis associated with good expansion. Longitudinalanalysis of post-treatment samples identified increased CXCR3– classical monocytes in all groups as CAR-T numbers waned. Together, our data uncovermediators of CAR-T biology and correlates of expansion that could be utilized to advanceimmunotherapies for solid tumor patients.

DOI: 10.1016/j.ccell.2023.11.011

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00402-6