CD19 CAR-T Cells(The Second Hospital of Shandong University)

The point-of-care, automated manufacturing of chimeric antigen receptor (CAR) T cells can reduce the waiting window and increase the therapy accessibility to patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) as compared with commercially available drug products (DPs). We conducted a phase 1/2 trial (NCT04787263) on the use of second-generation (4.1BB), CD19-CAR T cells, for the treatment of patients with BCP-ALL with either first relapse and very-high-risk (VHR) characteristics or second/subsequent relapse and rapidly progressing disease. CAR T cells were manufactured with a 12-day process using CliniMACS Prodigy, from a fresh apheresis and infused fresh. Three dose levels were tested in the phase 1: 1.0, 2.0, and 3.0×106 CAR+ T cells/kg. Nineteen patients were enrolled, 13 (68%) in first VHR relapse. The designed dose was always successfully produced. No dose-limiting toxicities were observed in the phase 1. Grade 1 to 2 cytokine release syndrome was observed in 13 (68%) patients. Grade 1 to 2 immune effector cell–associated neurotoxicity syndrome occurred in 2 patients and resolved spontaneously. All patients achieved bone marrow complete remission (CR) with negative minimal residual disease. Eight patients (42%) received hematopoietic stem cell transplantation (HSCT) consolidation. Overall, CR was maintained in 13 of 19 patients (68%), 7 of whom having received HSCT. Importantly, all but 1 patient treated with 3.0×106 CAR+ T cells/kg maintained CR. The 3-year event-free survival and overall survival of the whole cohort are 68% and 83%, respectively. Our data suggest that the point-of-care manufacturing of autologous, anti-CD19 CAR T cells can successfully treat patients with BCP-ALL including those with first relapse and VHR characteristics.

Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are complications of CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy. The Endothelial Activation and Stress Index (EASIX) and modified EASIX (m-EASIX) scores have been retrospectively proven to be predictive of CRS and ICANS in adult CAR T-cell recipients. However, these scores have not been evaluated in pediatric cohorts. We retrospectively report on 76 pediatric and adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia treated with CD19-CAR T cells at St. Jude Children’s Research Hospital or Johns Hopkins Hospital. Data included patient, disease, and treatment characteristics. EASIX and m-EASIX scores were calculated at days –5 before, 0, and +3 after CAR T-cell infusion. CRS and ICANS occurred in 47 and 17 patients, respectively. At all evaluated time points, the median EASIX scores were higher for patients who developed severe CRS and any grade ICANS, and the median m-EASIX scores were higher in patients who developed severe CRS and severe ICANS than those with no/mild CRS/ICANS. Receiver operating characteristic curve analysis showed that both scores were strong predictors of CRS, especially severe CRS, at all time points. Any grade and severe ICANS were best predicted by both scores at day +3. m-EASIX uniformly outperformed EASIX, except for predicting any grade ICANS. Our results validate the potential utility of EASIX and m-EASIX scores for predicting CAR T-cell–related complications for pediatric and AYA patients.