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

被引：38

作者：

del Bufalo, Francesca ^{[1
]}

Becilli, Marco ^{[1
]}

Rosignoli, Chiara ^{[1
]}

De Angelis, Biagio ^{[1
]}

Algeri, Mattia ^{[1
]}

Hanssens, Linda ^{[2
]}

Gunetti, Monica ^{[3
]}

Iacovelli, Stefano ^{[3
]}

Li Pira, Giuseppina ^{[1
]}

Girolami, Elia ^{[1
]}

Leone, Giovanna ^{[4
]}

Lazzaro, Stefania ^{[4
]}

Bertaina, Valentina ^{[1
]}

Sinibaldi, Matilde ^{[1
]}

Di Cecca, Stefano ^{[1
]}

Iaffaldano, Laura ^{[1
]}

Kunkele, Annette ^{[5
,6
,7
]}

Boccieri, Emilia ^{[1
]}

Del Baldo, Giada ^{[1
]}

Pagliara, Daria ^{[1
]}

Merli, Pietro ^{[1
]}

Carta, Roberto ^{[1
]}

Quintarelli, Concetta ^{[1
,8
]}

Locatelli, Franco ^{[1
,9
,10
]}

机构：

[1] Bambino Gesu Pediat Hosp, Ist Ricovero & Cura Carattere Sci IRCCS, Dept Hematol Oncol Cell & Gene Therapy, Rome, Italy

[2] Miltenyi Biomed, Bergisch Gladbach, Germany

[3] Good Mfg Practice Facil, Officina Farmaceut, Rome, Italy

[4] Bambino Gesu Pediat Hosp, Dept Labs, Transfus Unit, IRCCS, Rome, Italy

[5] Charite Univ med Berlin, Dept Pediat Oncol & Hematol, Berlin, Germany

[6] Humboldt Univ, Freie Univ Berlin, Berlin, Germany

[7] Berlin Inst Hlth, Berlin, Germany

[8] Univ Naples Federico II, Dept Clin Med & Surg, Naples, Italy

[9] Univ Cattolica Sacro Cuore, Dept Life Sci & Publ Hlth, Rome, Italy

[10] Bambino Gesu Pediat Hosp, Dept Hematol Oncol Cell & Gene Therapy, IRCCS, Piazza S Onofrio 4, I-00165 Rome, Italy

来源：

BLOOD | 2023年 / 142卷 / 02期

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; TRANSPLANTATION;

D O I：

10.1182/blood.2023020023

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 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 second-generation (4.1BB) CD19-directed 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 March 2021 and October 2022. Doses ranged between 1.0 x 10(6) and 3.0 x 10(6) CAR-T cells per kg. The toxicity profile was comparable with that of autologous CAR-T cells, characterized mainly by cytopenia, cytokine release syndrome (maximum grade 1), and grade 2 immune-effector cell-associated neurotoxicity syndrome. One case of acute graft-versus-host disease (GVHD) occurred and was rapidly controlled with steroids and ruxolitinib. None of the other patients, including 3 given ALLO-CAR-T cells from an HLA-haploidentical 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 absence of minimal residual disease in the bone marrow. With a median follow-up of 12 months (range, 5-21), 8 of 13 patients maintained CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly refractory BCP-ALL relapsing after allo-HSCT without showing increased toxicity as compared with autologous CAR-T cells.

引用

页码：146 / 157

页数：12

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