Memory stem T cells modified with a redesigned CD30-chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma
Por:
Alvarez-Fernandez, C, Escriba-Garcia, L, Caballero, AC, Escudero-Lopez, E, Ujaldon-Miro, C, Montserrat-Torres, R, Pujol-Fernandez, P, Sierra, J, Briones, J
Publicada:
1 ene 2021
Resumen:
Objectives Adoptive cell therapy (ACT) with mature T cells modified with a chimeric antigen receptor has demonstrated improved outcome for B-cell malignancies. However, its application for others such as Hodgkin lymphoma remains a clinical challenge. CD30 antigen, expressed in Hodgkin lymphoma cells, is absent in most healthy tissues, representing an ideal target of ACT for this disease. Despite that, efficacy of CD30-chimeric antigen receptor (CAR) T cells for Hodgkin lymphoma remains modest. Here, we have developed and tested a novel CD30-CAR T to improve efficacy of CD30-CAR therapy, using a targeting epitope within the non-cleavable part of CD30 receptor, and memory stem T cells (T-SCM) to improve engraftment, persistence and antitumor activity.
Methods TSCM-like cultures were generated and expanded ex vivo and transduced at day 1 or 2 with a lentiviral vector encoding the CD30-CAR. Therapeutic in vivo experiments were performed using NSG mice injected with L540 (sc) or L428 (iv) and treated with CD30-CAR T cells when the tumor was established.
Results CD30-CAR TSCM-like cells generated and expanded ex vivo, despite CD30 expression and fratricide killing of CD30(+) CAR T cells, were not impaired by soluble CD30 and completely eradicated Hodgkin lymphoma in vivo, showing high persistence and long-lasting immunity. In addition, highly enriched CD30-CAR TSCM-like products confer a survival advantage in vivo, in contrast to more differentiated CAR T cells, with higher tumor infiltration and enhanced antitumor effect.
Conclusion This study supports the use of a refined CD30-CAR T cells with highly enriched TSCM-like products to improve clinical efficacy of CAR T for Hodgkin lymphoma.
Filiaciones:
Alvarez-Fernandez, C:
Hosp Santa Creu & Sant Pau, Hematol Serv, Mas Casanovas 90, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau, Lab Expt Hematol IIB, Barcelona, Spain
Jose Carreras Leukemia Res Inst, Barcelona, Spain
Escriba-Garcia, L:
Hosp Santa Creu & Sant Pau, Hematol Serv, Mas Casanovas 90, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau, Lab Expt Hematol IIB, Barcelona, Spain
Jose Carreras Leukemia Res Inst, Barcelona, Spain
Caballero, AC:
Hosp Santa Creu & Sant Pau, Hematol Serv, Mas Casanovas 90, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau, Lab Expt Hematol IIB, Barcelona, Spain
Jose Carreras Leukemia Res Inst, Barcelona, Spain
Autonomous Univ Barcelona, Barcelona, Spain
Escudero-Lopez, E:
Hosp Santa Creu & Sant Pau, Hematol Serv, Mas Casanovas 90, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau, Lab Expt Hematol IIB, Barcelona, Spain
Jose Carreras Leukemia Res Inst, Barcelona, Spain
Autonomous Univ Barcelona, Barcelona, Spain
Ujaldon-Miro, C:
Hosp Santa Creu & Sant Pau, Hematol Serv, Mas Casanovas 90, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau, Lab Expt Hematol IIB, Barcelona, Spain
Jose Carreras Leukemia Res Inst, Barcelona, Spain
Autonomous Univ Barcelona, Barcelona, Spain
Montserrat-Torres, R:
Hosp Santa Creu & Sant Pau, Hematol Serv, Mas Casanovas 90, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau, Lab Expt Hematol IIB, Barcelona, Spain
Jose Carreras Leukemia Res Inst, Barcelona, Spain
Pujol-Fernandez, P:
Hosp Santa Creu & Sant Pau, Hematol Serv, Mas Casanovas 90, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau, Lab Expt Hematol IIB, Barcelona, Spain
Jose Carreras Leukemia Res Inst, Barcelona, Spain
Sierra, J:
Hosp Santa Creu & Sant Pau, Hematol Serv, Mas Casanovas 90, Barcelona 08041, Spain
Jose Carreras Leukemia Res Inst, Barcelona, Spain
Autonomous Univ Barcelona, Barcelona, Spain
Briones, J:
Hosp Santa Creu & Sant Pau, Hematol Serv, Mas Casanovas 90, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau, Lab Expt Hematol IIB, Barcelona, Spain
Jose Carreras Leukemia Res Inst, Barcelona, Spain
Autonomous Univ Barcelona, Barcelona, Spain
Green Published, gold
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