Stock Sophia, Bücklein Veit L, Blumenberg Viktoria, Magno Giulia, Emhardt Alica-Joana, Holzem Alessandra M E, Cordas Dos Santos David M, Schmidt Christian, Grießhammer Stefanie, Frölich Lisa, Kobold Sebastian, von Bergwelt-Baildon Michael, Rejeski Kai, Subklewe Marion
Department of Medicine III LMU University Hospital LMU Munich Munich Germany.
Division of Clinical Pharmacology, Department of Medicine IV LMU University Hospital, LMU Munich Munich Germany.
Hemasphere. 2025 Jan 13;9(1):e70062. doi: 10.1002/hem3.70062. eCollection 2025 Jan.
Immune deficits after CD19 chimeric antigen receptor (CAR) T-cell therapy can be long-lasting, predisposing patients to infections and non-relapse mortality. In B-cell non-Hodgkin lymphoma (B-NHL), the prognostic impact of immune reconstitution (IR) remains ill-defined, and detailed cross-product comparisons have not been performed to date. In this retrospective observational study, we longitudinally characterized lymphocyte subsets and immunoglobulin levels in 105 B-NHL patients to assess patterns of immune recovery arising after CD19 CAR-T. Three key IR criteria were defined as CD4 T helper (T) cells > 200/µL, any detectable B cells, and serum immunoglobulin G (IgG) levels >4 g/L. After a median follow-up of 24.6 months, 38% of patients displayed T cells, 11% showed any B cells, and 41% had IgG recovery. Notable product-specific differences emerged, including deeper T cell aplasia with CD28z- versus longer B-cell aplasia with 41BBz-based products. Patients with any IR recovery experienced extended progression-free survival (PFS) (median 20.8 vs. 1.7 months, < 0.0001) and overall survival (OS) (34.9 vs. 4.0 months, < 0.0001). While landmark analysis at 90 days confirmed improved PFS in patients with any recovery (34.9 vs. 8.6 months, = 0.005), no significant OS difference was noted. Notably, 72% of patients with refractory disease never displayed recovery of any IR criteria. Early progressors showed diminished IR at the time of progression/relapse compared to patients with late progression/recurrence (after Day 90). Our results highlight the profound immune deficits observed after CD19 CAR-T and shed light on the intersection of IR and efficacy in B-NHL. Importantly, IR was impaired considerably postprogression, carrying significant implications for subsequent T-cell-engaging therapies and treatment sequencing.
CD19嵌合抗原受体（CAR）T细胞治疗后的免疫缺陷可能会长期存在，使患者易发生感染和非复发死亡率。在B细胞非霍奇金淋巴瘤（B-NHL）中，免疫重建（IR）的预后影响仍不明确，迄今为止尚未进行详细的交叉产品比较。在这项回顾性观察研究中，我们纵向分析了105例B-NHL患者的淋巴细胞亚群和免疫球蛋白水平，以评估CD19 CAR-T治疗后出现的免疫恢复模式。定义了三个关键的IR标准，即CD4辅助性T（T）细胞>200/µL、任何可检测到的B细胞以及血清免疫球蛋白G（IgG）水平>4 g/L。中位随访24.6个月后，38%的患者T细胞恢复，11%的患者出现任何B细胞，41%的患者IgG恢复。出现了显著的产品特异性差异，包括基于CD28z的产品T细胞再生障碍更严重，而基于41BBz的产品B细胞再生障碍持续时间更长。任何IR恢复的患者无进展生存期（PFS）延长（中位20.8个月对1.7个月，<0.0001），总生存期（OS）延长（34.9个月对4.0个月，<0.0001）。虽然90天的标志性分析证实任何恢复的患者PFS有所改善（34.9个月对8.6个月，=0.005），但未观察到显著的OS差异。值得注意的是，72%的难治性疾病患者从未显示任何IR标准的恢复。与晚期进展/复发患者（第90天后）相比，早期进展者在进展/复发时IR减弱。我们的结果突出了CD19 CAR-T治疗后观察到的严重免疫缺陷，并揭示了B-NHL中IR与疗效的交叉点。重要的是，进展后IR明显受损，这对随后的T细胞参与治疗和治疗顺序具有重要意义。
