Donor-Derived CD19 CAR Cytokine Induced Killer (CIK) Cells Engineered with Sleeping Beauty Transposon for Relapsed B-Cell Acute Lymphoblastic Leukemia (B-ALL)

作者：Chiara F. Magnani, Giuseppe Gaipa, Daniela Belotti, Giada Matera, Sarah Tettamanti, Benedetta Cabiati, Chiara Buracchi, Grazia Fazio, Silvia Zaninelli, Silvia Rigamonti, Stefania Cesana, Valentina Colombo, Giovanni Cazzaniga, Attilio Rovelli, Adriana Balduzzi, Sara Napolitano, Fabrizio Benedicenti, Eugenio Montini, Gian Maria Borleri, Silvia Ferrari, Giuseppe Gritti, Federico Lussana, Martino Introna, Alessandro Rambaldi, Giuseppe Dastoli, Andrea Biondi · 发表于：Blood · 年份：2019 · DOI：10.1182/blood-2019-125894 · 被引用次数：10 · 研究领域：CAR-T cell therapy research、Viral Infectious Diseases and Gene Expression in Insects

Background Immunotherapy using patient-derived CAR T cells has achieved complete remission and durable response in highly refractory populations. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability. Allogeneic Cytokine Induced Killer (CIK) cells, a T-cell population characterized by the enrichment of CD3+CD56+ cells, have demonstrated a high profile of safety in acute lymphoblastic leukemia (ALL) patients (Introna M et al. Biol Blood Marrow Transplant. 2017). CIK cells could be easily engineered by the non-viral Sleeping Beauty (SB) transposon for the clinical application (Magnani CF et al, Hum Gene Ther. 2018, Biondi A et al. J Autoimmun. 2017). Methods CIK cells were generated from 50 ml of donor-derived peripheral blood (PB) by electroporation with the GMP-grade CD19.CAR/pTMNDU3 and pCMV-SB11 plasmids according to the method enclosed in the filed patent EP20140192371. After lymphodepletion with Fludarabine (30 mg/m2/day) x 4 days and Cyclophosphamide (300 mg/m2/day) x 2 days, CARCIK-CD19 were infused in pediatric and adult B-cell ALL (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT). The clinical trial follows a four-dose escalation scheme (1x106, 3x106, 7.5x106 and 15x106 transduced CAR+ T cells/kg) using the novel Bayesian Optimal Interval Design (BOIN). During the cell manufacturing period, bridging anti leukemic therapy from patient registration to the beginning o...