Simultaneous secretion of a PD-L1 x 4-1BB bispecific antibody improves antileukemic efficacy of STAb-T cells secreting a CD19-specific T-cell engager
Por:
M. GÓMEZ-ROSEL, L. RUBIO-PÉREZ, I. ZAGORAC, C. DOMÍNGUEZ-ALONSO, L. DÍEZ-ALONSO, O. HANGIU, R. NAVARRO, R. TORRES-RUÍZ, S. RODRÍGUEZ-PERALES, F. BLANCO, M. COMPTE, L. ALVAREZ-VALLINA and B. BLANCO
Publicada:
31 dic 2025
Resumen:
Adoptive therapy with CAR-T cells and systemic administration of bispecific T-cell engagers (TCE) have achieved unprecedented success in the treatment of relapsed/refractory (R/R) B-cell malignancies. However, high relapse rates remain a major challenge. STAb (Secretion of T cell-redirecting bispecific Antibodies)-T-cell immunotherapy represents a promising alternative by enabling both polyclonal T-cell recruitment and sustained bispecific antibody release. Here, we describe an evolution of STAb-T19 therapy, which has demonstrated superior outcomes to those of CAR-T-19 cells in preclinical models of B-ALL, on the basis of the simultaneous secretion of two bispecific antibodies: a CD19 x CD3 TCE and a PD-L1 x 4-1BB bsAb. The combined approach aims to increase the antitumor efficacy of STAb-T19 cells by blocking the PD-1/PD-L1 axis with conditional 4-1BB costimulation to ensure the long-term persistence of STAb-T cells. Preclinical data show that this combination improves cytotoxic activity and prolongs antileukemic efficacy compared with low-dose single STAb-T therapy. Our findings suggest that the integration of PD-L1 x 4-1BB bsAbs into STAb-T19 therapy may maximize efficacy, thereby opening a promising avenue to address resistance and relapse in B-ALL. Moreover, this approach may pave the way for the development of next-generation cell-based therapies for hematologic and solid malignancies.
Filiaciones:
M. GÓMEZ-ROSEL:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UNICA, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, Hosp Mar Res Inst Barcelona HMRIB, CNIO HMRIB Canc Immunotherapy Clin Res Unit, Madrid, Spain
Leadartis SL, Dept Antibody Engn, QUBE Technol Pk, Tres Cantos, Madrid, Spain
L. RUBIO-PÉREZ:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UNICA, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, Hosp Mar Res Inst Barcelona HMRIB, CNIO HMRIB Canc Immunotherapy Clin Res Unit, Madrid, Spain
I. ZAGORAC:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UNICA, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, Hosp Mar Res Inst Barcelona HMRIB, CNIO HMRIB Canc Immunotherapy Clin Res Unit, Madrid, Spain
C. DOMÍNGUEZ-ALONSO:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UNICA, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, Hosp Mar Res Inst Barcelona HMRIB, CNIO HMRIB Canc Immunotherapy Clin Res Unit, Madrid, Spain
L. DÍEZ-ALONSO:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UNICA, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, Hosp Mar Res Inst Barcelona HMRIB, CNIO HMRIB Canc Immunotherapy Clin Res Unit, Madrid, Spain
O. HANGIU:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UNICA, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Leadartis SL, Dept Antibody Engn, QUBE Technol Pk, Tres Cantos, Madrid, Spain
R. NAVARRO:
Leadartis SL, Dept Antibody Engn, QUBE Technol Pk, Tres Cantos, Madrid, Spain
R. TORRES-RUÍZ:
Ctr Nacl Invest Oncol CNIO, Human Canc Genet Program, Mol Cytogenet Grp, Madrid, Spain
S. RODRÍGUEZ-PERALES:
Ctr Nacl Invest Oncol CNIO, Human Canc Genet Program, Mol Cytogenet Grp, Madrid, Spain
:
CSIC, Inst Biomed Valencia IBV, Valencia, Spain
Ctr Invest Principe Felipe CIPF, Unidad Asociada IBV, Valencia, Spain
M. COMPTE:
Leadartis SL, Dept Antibody Engn, QUBE Technol Pk, Tres Cantos, Madrid, Spain
L. ALVAREZ-VALLINA:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UNICA, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, Hosp Mar Res Inst Barcelona HMRIB, CNIO HMRIB Canc Immunotherapy Clin Res Unit, Madrid, Spain
Banc Sang i Teixits, Barcelona, Spain
B. BLANCO:
Hosp Univ 12 Octubre, Dept Immunol, Canc Immunotherapy Unit UNICA, Madrid, Spain
Inst Invest Sanitaria Hosp 12 Octubre imas12, Immuno Oncol & Immunotherapy Grp, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, Hosp Mar Res Inst Barcelona HMRIB, CNIO HMRIB Canc Immunotherapy Clin Res Unit, Madrid, Spain
Inst Salud Carlos III, Dept Desarrollo Medicamentos Terapias Avanzadas, Madrid, Spain
Green Accepted, gold
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