Engineered cellular therapy with CD19-targeting chimeric antigen receptor T cells (CAR-Ts) has revolutionized outcomes for patients with relapsed/refractory large B-cell lymphoma (LBCL), but the cellular and molecular features associated with response remain largely unresolved. We analyzed serial peripheral blood samples ranging from the day of apheresis (day –28/baseline) to 28 days after CAR-T infusion from 50 patients with LBCL treated with axicabtagene ciloleucel by integrating single-cell RNA and T-cell receptor sequencing, flow cytometry, and mass cytometry to characterize features associated with response to CAR-T. Pretreatment patient characteristics associated with response included the presence of B cells and increased absolute lymphocyte count to absolute monocyte count ratio (ALC/AMC). Infusion products from responders were enriched for clonally expanded, highly activated CD8+ T cells. We expanded these observations to 99 patients from the ZUMA-1 cohort and identified a subset of patients with elevated baseline B cells, 80% of whom were complete responders. We integrated B-cell proportion ≥0.5% and ALC/AMC ≥1.2 into a 2-factor predictive model and applied this model to the ZUMA-1 cohort. Estimated progression-free survival at 1 year in patients meeting 1 or both criteria was 65% vs 31% for patients meeting neither criterion. Our results suggest that patients’ immunologic state at baseline affects the likelihood of response to CAR-T through both modulation of the T-cell apheresis product composition and promoting a more favorable circulating immune compartment before therapy. These baseline immunologic features, measured readily in the clinical setting before CAR-T, can be applied to predict response to therapy.

中文翻译：

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基线免疫状态和 T 细胞克隆动力学与大 B 细胞淋巴瘤对 CAR-T 疗法的持久反应相关


靶向 CD19 的嵌合抗原受体 T 细胞 （CAR-T） 的工程细胞疗法彻底改变了复发/难治性大 B 细胞淋巴瘤 （LBCL） 患者的预后，但与反应相关的细胞和分子特征在很大程度上仍未得到解决。我们分析了 50 例接受 axicabtagene ciloleucel治疗的 LBCL 患者从单采术当天（-28 天/基线）到 CAR-T 输注后 28 天的系列外周血样本，通过整合单细胞 RNA 和 T 细胞受体测序、流式细胞术和质谱细胞术来表征与对 CAR-T 的反应相关的特征。与反应相关的治疗前患者特征包括 B 细胞的存在和绝对淋巴细胞计数与绝对单核细胞计数比 （ALC/AMC） 的增加。来自反应者的输注产物富集了克隆扩增、高度激活的 CD8+ T 细胞。我们将这些观察结果扩展到 ZUMA-1 队列中的 99 名患者，并确定了基线 B 细胞升高的患者亚群，其中 80% 是完全缓解者。我们将 B 细胞比例 ≥0.5% 和 ALC/AMC ≥1.2 整合到一个 2 因素预测模型中，并将该模型应用于 ZUMA-1 队列。满足 1 项或两项标准的患者 1 年估计无进展生存率为 65%，而满足 1 项标准的患者为 31%。我们的结果表明，患者基线时的免疫状态通过调节 T 细胞单采产物组成和促进治疗前更有利的循环免疫隔室来影响对 CAR-T 反应的可能性。这些基线免疫学特征在 CAR-T 之前很容易在临床环境中测量，可用于预测对治疗的反应。