Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH.
Blood Adv. 2024 Jun 25;8(12):3140-3153. doi: 10.1182/bloodadvances.2023012073.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Robust biomarkers and a complete understanding of CAR T-cell function in the postinfusion phase remain limited. Here, we used a 37-color spectral flow cytometry panel to perform high dimensional single-cell analysis of postinfusion samples in 26 patients treated with CD28 costimulatory domain containing commercial CAR T cells for NHL and focused on computationally gated CD8+ CAR T cells. We found that the presence of postinfusion Programmed cell death protein 1 (PD-1)+ CD8+ CAR T cells at the day 14 time point highly correlated with the ability to achieve complete response (CR) by 6 months. Further analysis identified multiple subtypes of CD8+ PD-1+ CAR T cells, including PD-1+ T cell factor 1 (TCF1)+ stem-like CAR T cells and PD-1+ T-cell immunoglobulin and mucin-domain containing-3 (TIM3)+ effector-like CAR T cells that correlated with improved clinical outcomes such as response and progression-free survival. Additionally, we identified a subset of PD-1+ CD8+ CAR+ T cells with effector-like function that was increased in patients who achieved a CR and was associated with grade 3 or higher immune effector cell-associated neurotoxicity syndrome. Here, we identified robust biomarkers of response to CD28 CAR T cells and highlight the importance of PD-1 positivity in CD8+ CAR T cells after infusion in achieving CR.
嵌合抗原受体 (CAR) T 细胞疗法彻底改变了复发/难治性 B 细胞非霍奇金淋巴瘤 (NHL) 的治疗方法。在输注后阶段，强大的生物标志物和对 CAR T 细胞功能的全面了解仍然有限。在这里，我们使用 37 色光谱流式细胞术面板对 26 例接受 CD28 共刺激结构域包含商业 CAR T 细胞治疗 NHL 的患者输注后的样本进行高维单细胞分析，并专注于计算门控的 CD8+ CAR T 细胞。我们发现，在第 14 天时间点输注后存在程序性死亡蛋白 1 (PD-1)+CD8+CAR T 细胞与在 6 个月内实现完全缓解 (CR) 的能力高度相关。进一步分析确定了多种 CD8+PD-1+CAR T 细胞亚型，包括 PD-1+T 细胞因子 1 (TCF1)+ 干细胞样 CAR T 细胞和 PD-1+T 细胞免疫球蛋白和粘蛋白结构域包含 3 (TIM3)+效应样 CAR T 细胞，与改善的临床结果相关，如反应和无进展生存期。此外，我们鉴定出一组具有效应样功能的 PD-1+CD8+CAR+T 细胞，在达到 CR 的患者中增加，与 3 级或更高的免疫效应细胞相关的神经毒性综合征相关。在这里，我们确定了对 CD28 CAR T 细胞反应的强大生物标志物，并强调了输注后 PD-1 阳性在 CD8+CAR T 细胞中实现 CR 的重要性。
