CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study

Abstract CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.

摘要 靶向CD19的嵌合抗原受体T细胞（CAR - T）在复发/难治性套细胞淋巴瘤（MCL）患者中取得了较高的缓解率。然而，其应用伴有显著的毒性、复发问题以及广泛适用性不明确等情况。临床前和临床数据支持依鲁替尼对单采产品适应性、CAR - T细胞扩增以及毒性具有有益的协同作用。在2期TARMAC研究中，我们评估了限时使用依鲁替尼与CTL019 CAR - T联合治疗20例MCL患者的情况。依鲁替尼在白细胞单采前开始使用，并在CAR - T细胞制备过程中持续使用，在CAR - T细胞输注后至少持续6个月。先前治疗的中位线数为2；50%的患者先前曾接触过布鲁顿酪氨酸激酶抑制剂（BTKi）。主要终点是输注后4个月的完全缓解（CR）率，次要终点包括安全性以及基于TP53异常的亚组分析。主要终点达到；80%的患者显示完全缓解，其中分别有70%和40%的患者通过流式细胞术和分子方法显示可测量残留疾病呈阴性。在中位随访13个月时，估计12个月无进展生存率为75%，总生存率为100%。15例患者（75%）发生细胞因子释放综合征；12例（55%）为1 - 2级，3例（20%）为3级。2例患者（10%）观察到可逆的1 - 2级神经毒性。无论先前是否接触过BTKi或是否存在TP53突变，疗效均得以保持。深度缓解与CAR - T细胞强劲扩增以及基线T细胞耗竭程度较低的表型相关。总体而言，BTKi与T细胞重定向免疫疗法联合的安全性和有效性似乎很有前景，值得进一步探索。该试验在www.ClinicalTrials.gov注册，编号为#NCT04234061。