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

被引：30

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

共 30 条

[11] Donor CD19 CART cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity
Ghosh, Arnab
Smith, Melody
James, Scott E.
Davila, Marco L.
Velardi, Enrico
Argyropoulos, Kimon V.
Gunset, Gertrude
Perna, Fabiana
Kreines, Fabiana M.
Levy, Emily R.
Lieberman, Sophie
Jay, Hillary V.
Tuckett, Andrea Z.
Zakrzewski, Johannes L.
Tan, Lisa
Young, Lauren F.
Takvorian, Kate
Dudakov, Jarrod A.
Jenq, Robert R.
Hanash, Alan M.
Motta, Ana Carolina F.
Murphy, George F.
Liu, Chen
Schietinger, Andrea
Sadelain, Michel
van den Brink, Marcel R. M.
[J]. NATURE MEDICINE, 2017, 23 (02) : 242 - 249
[12] International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium
Harris, Andrew C.
Young, Rachel
Devine, Steven
Hogan, William J.
Ayuk, Francis
Bunworasate, Udomsak
Chanswangphuwana, Chantiya
Efebera, Yvonne A.
Holler, Ernst
Litzow, Mark
Ordemann, Rainer
Qayed, Muna
Renteria, Anne S.
Reshef, Ran
Woelfl, Matthias
Chen, Yi-Bin
Goldstein, Steven
Jagasia, Madan
Locatelli, Franco
Mielke, Stephan
Porter, David
Schechter, Tal
Shekhovtsova, Zhanna
Ferrara, James L. M.
Levine, John E.
[J]. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 2016, 22 (01) : 4 - 10
[13] Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells
Kebriaei, Partow
Singh, Harjeet
Huls, M. Helen
Figliola, Matthew J.
Bassett, Roland
Olivares, Simon
Jena, Bipulendu
Dawson, Margaret J.
Kumaresan, Pappanaicken R.
Su, Shihuang
Maiti, Sourindra
Dai, Jianliang
Moriarity, Branden
Forget, Marie-Andree
Senyukov, Vladimir
Orozco, Aaron
Liu, Tingting
McCarty, Jessica
Jackson, Rinelca N.
Moyes, Judy S.
Rondon, Gabriela
Qazilbash, Muzaffar
Ciurea, Stefan
Alousi, Amin
Nieto, Yago
Rezvani, Katy
Marin, David
Popat, Uday
Hosing, Chitra
Shpall, Elizabeth J.
Kantarjian, Hagop
Keating, Michael
Wierda, William
Do, Kim Anh
Largaespada, David A.
Lee, Dean A.
Hackett, Perry B.
Champlin, Richard E.
Cooper, Laurence J. N.
[J]. JOURNAL OF CLINICAL INVESTIGATION, 2016, 126 (09) : 3363 - 3376
[14] Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation
Kochenderfer, James N.
Dudley, Mark E.
Carpenter, Robert O.
Kassim, Sadik H.
Rose, Jeremy J.
Telford, William G.
Hakim, Frances T.
Halverson, David C.
Fowler, Daniel H.
Hardy, Nancy M.
Mato, Anthony R.
Hickstein, Dennis D.
Gea-Banacloche, Juan C.
Pavletic, Steven Z.
Sportes, Claude
Maric, Irina
Feldman, Steven A.
Hansen, Brenna G.
Wilder, Jennifer S.
Blacklock-Schuver, Bazetta
Jena, Bipulendu
Bishop, Michael R.
Gress, Ronald E.
Rosenberg, Steven A.
[J]. BLOOD, 2013, 122 (25) : 4129 - 4139
[15] ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells
Lee, Daniel W.
Santomasso, Bianca D.
Locke, Frederick L.
Ghobadi, Armin
Turtle, Cameron J.
Brudno, Jennifer N.
Maus, Marcela, V
Park, Jae H.
Mead, Elena
Pavletic, Steven
Go, William Y.
Eldjerou, Lamis
Gardner, Rebecca A.
Frey, Noelle
Curran, Kevin J.
Peggs, Karl
Pasquini, Marcelo
DiPersio, John F.
van den Brink, Marcel R. M.
Komanduri, Krishna, V
Grupp, Stephan A.
Neelapu, Sattva S.
[J]. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 2019, 25 (04) : 625 - 638
[16] Current concepts in the diagnosis and management of cytokine release syndrome
Lee, Daniel W.
Gardner, Rebecca
Porter, David L.
Louis, Chrystal U.
Ahmed, Nabil
Jensen, Michael
Grupp, Stephan A.
Mackall, Crystal L.
[J]. BLOOD, 2014, 124 (02) : 188 - 195
[17] The differential effects of tumor burdens on predicting the net benefits of ssCART-19 cell treatment on r/r B-ALL patients
Li, Minghao
Xue, Sheng-Li
Tang, Xiaowen
Xu, Jiayu
Chen, Suning
Han, Yue
Qiu, Huiying
Miao, Miao
Xu, Nan
Tan, Jingwen
Kang, Liqing
Yu, Zhou
Lou, Xiaoyan
Xu, Yang
Chen, Jia
Yan, Zhiqiang
Feng, Weixing
Wu, Depei
Yu, Lei
[J]. SCIENTIFIC REPORTS, 2022, 12 (01)
[18] ADOPTIVE IMMUNOTHERAPY EVALUATING ESCALATING DOSES OF DONOR LEUKOCYTES FOR RELAPSE OF CHRONIC MYELOID-LEUKEMIA AFTER BONE-MARROW TRANSPLANTATION - SEPARATION OF GRAFT-VERSUS-LEUKEMIA RESPONSES FROM GRAFT-VERSUS-HOST DISEASE
MACKINNON, S
PAPADOPOULOS, EB
CARABASI, MH
REICH, L
COLLINS, NH
BOULAD, F
CASTROMALASPINA, H
CHILDS, BH
GILLIO, AP
KERNAN, NA
SMALL, TN
YOUNG, JW
OREILLY, RJ
[J]. BLOOD, 1995, 86 (04) : 1261 - 1268
[19] Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients
Maschan, Michael
Caimi, Paolo F.
Reese-Koc, Jane
Sanchez, Gabriela Pacheco
Sharma, Ashish A.
Molostova, Olga
Shelikhova, Larisa
Pershin, Dmitriy
Stepanov, Alexey
Muzalevskii, Yakov
Suzart, Vinicius G.
Otegbeye, Folashade
Wald, David
Xiong, Ying
Wu, Darong
Knight, Adam
Oparaocha, Ibe
Ferencz, Beatrix
Roy, Andre
Worden, Andrew
Kruger, Winfried
Kadan, Michael
Schneider, Dina
Orentas, Rimas
Sekaly, Rafick-Pierre
de Lima, Marcos
Dropulic, Boro
[J]. NATURE COMMUNICATIONS, 2021, 12 (01)
[20] Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia
Maude, S. L.
Laetsch, T. W.
Buechner, J.
Rives, S.
Boyer, M.
Bittencourt, H.
Bader, P.
Verneris, M. R.
Stefanski, H. E.
Myers, G. D.
Qayed, M.
De Moerloose, B.
Hiramatsu, H.
Schlis, K.
Davis, K. L.
Martin, P. L.
Nemecek, E. R.
Yanik, G. A.
Peters, C.
Baruchel, A.
Boissel, N.
Mechinaud, F.
Balduzzi, A.
Krueger, J.
June, C. H.
Levine, B. L.
Wood, P.
Taran, T.
Leung, M.
Mueller, K. T.
Zhang, Y.
Sen, K.
Lebwohl, D.
Pulsipher, M. A.
Grupp, S. A.
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2018, 378 (05) : 439 - 448

← 1 2 3 →