Maurer Katie, Grabski Isabella N, Houot Roch, Gohil Satyen H, Miura Shogo, Redd Robert, Lyu Haoxiang, Lu Wesley, Arihara Yohei, Budka Justin, McDonough Mikaela, Ansuinelli Michela, Reynolds Carol, Jacene Heather, Li Shuqiang, Livak Kenneth J, Ritz Jerome, Miles Brodie, Mattie Mike, Neuberg Donna S, Irizarry Rafael A, Armand Philippe, Wu Catherine J, Jacobson Caron
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Harvard Medical School, Boston, MA.
Blood. 2024 Dec 12;144(24):2490-2502. doi: 10.1182/blood.2024024381.
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.
使用靶向CD19的嵌合抗原受体T细胞（CAR-T）进行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）患者的治疗结果，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例接受阿基仑赛治疗的LBCL患者从采集血细胞单采术当天（第-28天/基线）到CAR-T输注后28天的连续外周血样本，通过整合单细胞RNA和T细胞受体测序、流式细胞术和质谱流式细胞术来表征与CAR-T反应相关的特征。与反应相关的预处理患者特征包括B细胞的存在以及绝对淋巴细胞计数与绝对单核细胞计数之比（ALC/AMC）增加。反应者的输注产物富含克隆扩增、高度活化的CD8+T细胞。我们将这些观察结果扩展到来自ZUMA-1队列的99例患者，并确定了一组基线B细胞升高的患者，其中80%为完全缓解者。我们将B细胞比例≥0.5%和ALC/AMC≥1.2整合到一个双因素预测模型中，并将该模型应用于ZUMA-1队列。符合1项或2项标准的患者1年时的估计无进展生存率为65%，而两项标准均不符合的患者为31%。我们的结果表明，患者基线时的免疫状态通过调节T细胞采集产物组成和在治疗前促进更有利的循环免疫区室来影响对CAR-T反应的可能性。这些在CAR-T治疗前的临床环境中易于测量的基线免疫特征可用于预测治疗反应。
