用于治疗难治性多发性骨髓瘤的学术 BCMA-CART ARI0002h 的疗效和安全性的生物标志物。

Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma.

机构信息

Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain.

Hospital Universitari Son Espases, IDISBA, Palma de Mallorca, Spain.

出版信息

Clin Cancer Res. 2024 May 15;30(10):2085-2096. doi: 10.1158/1078-0432.CCR-23-3759.

DOI:10.1158/1078-0432.CCR-23-3759

PMID:38466644

Abstract

PURPOSE

B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial.

PATIENTS AND METHODS

We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes.

RESULTS

At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse.

CONCLUSIONS

Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.

摘要

目的

B 细胞成熟抗原（BCMA）-嵌合抗原受体 T 细胞（CART）改善了复发/难治性多发性骨髓瘤患者接受常规治疗的结果。然而，CART 治疗的高需求和昂贵成本可能对医疗系统来说是不可持续的。学术性 CART 有可能克服这些问题。此外，需要确定和解决反应生物标志物和耐药机制，以提高疗效和患者选择。在这里，我们报告了 60 例接受学术性 BCMA-CART、ARI0002h 治疗的患者在 CARTBCMA-HCB-01 试验中的临床和辅助结果。

方法

我们在输注前后收集了单采术、最终产品、外周血和骨髓样本。我们通过下一代流式细胞术评估了 BCMA、T 细胞亚群、CART 动力学和抗体、B 细胞衰竭、细胞因子和可测量的残留疾病，并将这些与临床结果相关联。

结果

截至 2023 年 3 月 17 日的截止日期，中位随访时间为 23.1 个月（95%置信区间，9.2-37.1），前 3 个月的总体缓解率为 95%（95%置信区间，89.5-100）；90%的患者发生细胞因子释放综合征（CRS）（5%为 3 级及以上），2 例患者（3%）发生 1 级免疫效应细胞相关神经毒性综合征。中位无进展生存期为 15.8 个月（95%置信区间，11.5-22.4）。表面 BCMA 对反应或生存没有预测作用，但可溶性 BCMA 与较差的临床结果和 CRS 严重程度相关。单采术中的激活标志物 HLA-DR 与更长的无进展生存期相关，而耗竭标志物的增加与更差的结果相关。ARI0002h 的动力学和 B 细胞衰竭的丧失与复发无相关性。