Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel.
Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel.
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DOI：
10.1158/1078-0432.ccr-20-1434
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发表时间：
2020-09-15
期刊：
影响因子：
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通讯作者：
Davila ML
中科院分区：
文献类型：
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作者：
Faramand R;Jain M;Staedtke V;Kotani H;Bai R;Reid K;Lee SB;Spitler K;Wang X;Cao B;Pinilla J;Lazaryan A;Khimani F;Shah B;Chavez JC;Nishihori T;Mishra A;Mullinax J;Gonzalez R;Hussaini M;Dam M;Brandjes BD;Bachmeier CA;Anasetti C;Locke FL;Davila ML
过继性 T 细胞疗法的挑战之一是产生免疫介导的毒性，包括细胞因子释放综合征 (CRS) 和神经毒性 (NT)。我们的目的是在接受标准护理 CD19 靶向 CAR T 细胞产品 (axicabtagene ciloleucel) 治疗的 75 名大 B 细胞淋巴瘤患者队列中，确定导致患者处于严重毒性或治疗相关死亡高风险的因素。在淋巴细胞清除化疗之前、CAR T 输注当天以及患者住院期间每天测量血清细胞因子和儿茶酚胺水平。在 CAR T 输注前一个月内进行肿瘤活检，以评估基因表达。我们发现治疗前白介素 6 水平与危及生命的 CRS 和 NT 之间存在关联。由于毒性风险与治疗前因素有关，我们假设肿瘤微环境（TME）可能影响CAR T细胞毒性。在治疗前患者肿瘤活检中，骨髓标记物的基因表达与较高的毒性相关。这些结果表明，促炎状态和不利的 TME 会预先使患者在 CAR T 细胞治疗后面临毒性风险。根据患者风险定制毒性管理策略可能会降低发病率和死亡率。
One of the challenges of adoptive T cell therapy is the development of immune mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment related death in a cohort of 75 patients with large B cell lymphoma treated with a standard of care CD19 targeted CAR T cell product (axicabtagene ciloleucel). Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within one month prior to CAR T infusion for evaluation of gene expression. We identified an association between pre-treatment levels of interleukin 6 and life-threatening CRS and NT. Since the risk of toxicity was related to pre-treatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T cell toxicity. In pre-treatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity. These results suggest that a pro-inflammatory state and an unfavorable TME pre-emptively put patients at risk for toxicity after CAR T cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.