Lussana Federico, Magnani Chiara F, Galimberti Stefania, Gritti Giuseppe, Gaipa Giuseppe, Belotti Daniela, Cabiati Benedetta, Napolitano Sara, Ferrari Silvia, Moretti Alex, Buracchi Chiara, Borleri Gian Maria, Rambaldi Benedetta, Rizzuto Giuliana, Grassi Anna, Paganessi Muriel, Meli Cristian, Tettamanti Sarah, Risca Giulia, Pais Giulia, Spinozzi Giulio, Benedicenti Fabrizio, Cazzaniga Giovanni, Capelli Chiara, Gotti Elisa, Introna Martino, Golay Josée, Montini Eugenio, Balduzzi Adriana, Valsecchi Maria Grazia, Dastoli Giuseppe, Rambaldi Alessandro, Biondi Andrea
Hematology and Bone Marrow Transplant Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
Department of Oncology and Hematology, University of Milan, Milan, Italy.
Blood Cancer J. 2025 Apr 3;15(1):54. doi: 10.1038/s41408-025-01260-6.
Non-viral engineering can ease CAR-T cell production and reduce regulatory and cost requirements. We utilized Sleeping Beauty transposon to engineer donor-derived anti-CD19.CD28.OX40.CD3zeta T cells differentiated in cytokine-induced killer (CARCIK-CD19) for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (alloHSCT). We report the results of CARCIK-CD19 observed in 36 patients (4 children and 32 adults) treated according to the final recommended dose. Cytokine release syndrome of grade 2 or lower occurred in 15 patients, ICANS grade 2 in 1 patient, and late-onset peripheral neurotoxicity of grade 3 in 2 patients. GVHD never occurred after treatment with allogeneic CARCIK-CD19. Complete remission was achieved by 30 out of 36 patients (83.3%), with MRD negativity in 89% of responders. With a median follow-up of 2.2 years, the 1-year overall survival was 57.0%, and event-free survival was 32.0%. The median duration of response at 1 year was 38.6%. CAR-T cells expanded rapidly after infusion and remained detectable for over 2 years. Integration site analysis after infusion showed a high clonal diversity. These data demonstrated that SB-engineered CAR-T cells are safe and induce durable remission in heavily pretreated patients with BCP-ALL relapsed after alloHSCT. Trial registration: The phase 1/2 and phase II trials are registered at www.clinicaltrials.gov as NCT#03389035 and NCT#05252403.
非病毒工程技术可简化嵌合抗原受体T细胞（CAR-T）的生产，并降低监管和成本要求。我们利用睡美人转座子对供体来源的抗CD19.CD28.OX40.CD3ζ T细胞进行工程改造，这些T细胞是在细胞因子诱导的杀伤细胞（CARCIK-CD19）中分化出来的，用于治疗异基因造血干细胞移植（alloHSCT）后复发的B细胞前体急性淋巴细胞白血病（BCP-ALL）患者。我们报告了根据最终推荐剂量治疗的36例患者（4名儿童和32名成人）中观察到的CARCIK-CD19的结果。15例患者发生2级或更低级别的细胞因子释放综合征，1例患者发生2级免疫效应细胞相关神经毒性综合征（ICANS），2例患者发生3级迟发性周围神经毒性。同种异体CARCIK-CD19治疗后从未发生移植物抗宿主病（GVHD）。36例患者中有30例（83.3%）实现完全缓解，89%的缓解者微小残留病（MRD）呈阴性。中位随访2.2年，1年总生存率为57.0%，无事件生存率为32.0%。1年时的中位缓解持续时间为38.6%。输注后CAR-T细胞迅速扩增，并在2年多的时间内仍可检测到。输注后的整合位点分析显示克隆多样性高。这些数据表明，经睡美人转座子工程改造的CAR-T细胞是安全的，并能在alloHSCT后复发的、经过大量预处理的BCP-ALL患者中诱导持久缓解。试验注册：1/2期和II期试验已在www.clinicaltrials.gov上注册，注册号分别为NCT#03389035和NCT#05252403。
