Work

Administration of Low-Dose, Subcutaneous (SC) Interleukin-2 (IL-2) Markedly Enhances the Pharmacokinetic (PK) Profile of Azercabtagene Zapreleucel (azer-cel), an Allogeneic Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy, without Compromising Safety and Early Evidence of Clinical Activity in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Who Have Relapsed after Prior CD19-Directed CAR T-Cell Products

Year: 2025

Type: article

Abstract: Azer-cel is a CD19-directed allogeneic CAR T-cell therapy where an anti-CD19 CAR is integrated into the T-cell receptor alpha constant (TRAC) locus using ARCUS nuclease technology, eliminating graft-versus-host disease (GvHD) risk. Azer-cel is currently being investigated in a Phase 1/1b study in r/r B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma. Here we report the interim results from the Phase 1b portion (r/r DLBCL). Patients with CD19+ r/r DLBCL after 2+ treatments without central nervous system disease , active infection, GvHD, or comorbidities were enrolled (NCT03666000). Prior stem cell transplant, bispecific antibody , and CD19 CAR T therapy were allowed. All patients received lymphodepletion with Aug/Cy (fludarabine 30 mg/m 2 /day and cyclophosphamide 750 mg/m 2 /day × 3 days) prior to azer-cel infusion (500 × 10⁶ cells) on Day 0. Twelve patients were treated; 7 (58%) had ³4 prior therapies, and all received prior CD19 CAR T. Adverse events were generally mild, with no Grade ³3 cytokine release syndrome (CRS) or GvHD. Serious Grade ³3 events occurred in 2 patients: immune effector cell-associated neurotoxicity (ICANS), disseminated intravascular coagulation , cytomegalovirus reactivation, and retroperitoneal hematoma in 1 patient, resulting in death; and febrile neutropenia in the other patient. Five (42%) patients responded to azer-cel, with 2 (17%) achieving complete response (CR) (Table 1). Preclinically, adding low-dose IL-2 enhanced azer-cel's ability to repeatedly kill target cells. Thus, the next cohort of patients received low-dose IL-2 (1 million IU SC daily, Days 1-14) after Aug/Cy lymphodepletion and azer-cel. IL-2 markedly improved CAR T expansion (Figure 1) without impacting safety, with 3 CRs reported in 4 evaluable patients, and 1 with ongoing response past 120 days. Administration of low-dose IL-2 after treatment with azer-cel and Aug/Cy lymphodepletion may provide clinical benefit with predictable and manageable toxicity and markedly improved PK (∼2 log increase in C max ).

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.340