Allogeneic, donor-derived, second-generation, CD19-CAR-T cell for the treatment of pediatric relapsed/refractory BCP-ALL

Autor: Francesca del Bufalo, Marco Becilli, Chiara Rosignoli, Biagio De Angelis, Mattia Algeri, Linda Hanssens, Monica Gunetti, Stefano Iacovelli, Giuseppina Li Pira, Elia Girolami, Giovanna Leone, Stefania Lazzaro, Valentina Bertaina, Matilde Sinibaldi, Stefano Di Cecca, Laura Iaffaldano, Annette Künkele, Emilia Boccieri, Giada Del Baldo, Daria Pagliara, Pietro Merli, Roberto Carta, Concetta Quintarelli, Franco Locatelli
Rok vydání: 2023
Předmět:
Zdroj: Blood Journal.
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.2023020023
Popis: Autologous CD19-directed chimeric antigen receptor (CAR)-T cells have shown unprecedented efficacy in children with relapsed/refractory B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). However, patients either relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT), or displaying profound lymphopenia and/or with rapidly progressing disease often cannot access autologous products. These hurdles may be overcome by allogeneic, donor-derived CAR-T cells. We tested donor-derived T-cells transduced with a 2nd-generation (4.1BB) CD19-CAR for treatment of patients with BCP-ALL, in a hospital exemption setting. Two constructs were tested: a retroviral construct incorporating the suicide gene inducible caspase-9 (CD19-CAR-Retro_ALLO) first and then a lentiviral construct and an automated, Prodigy®-based, manufacturing process (CD19-CAR-Lenti_ALLO). Thirteen children/young adults received ALLO-CAR T-cells between 03/2021 and 10/2022. Doses ranged between 1,0×106 and 3,0×106 CAR T-cells/kg. The toxicity profile was comparable to that of autologous CAR-T cells, characterized mainly by cytopenia, CRS (maximum grade 1) and grade 2 ICANS. One case of acute graft-versus-host disease (GvHD) occurred and was rapidly controlled by steroids and ruxolitinib. None of the other patients, including 3 infused with ALLO-CAR T cells from an HLA-haplo-identical donor, experienced GvHD. Two patients received ALLO-CAR T-cells before HSCT and showed a significant expansion of CAR T cells, without any sign of GvHD. All patients obtained complete remission (CR) with negativity of minimal residual disease in the BM; with a median follow-up of 12 months (range 5-21), 8/13 patients maintain CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly-refractory BCP-ALL relapsing after alloHSCT, without showing increased toxicity as compared to autologous CAR T cells.
Databáze: OpenAIRE
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