Venetoclax improves CD20 immunotherapy in a mouse model of MYC/BCL2 double-expressor diffuse large B-cell lymphoma
Keywords: 
B-lymphocytes
CD4-CD8 ratio
Drug evaluation
Preclinical
Hematologic neoplasms
Immunotherapy.
Issue Date: 
2023
Project: 
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-112994RB-I00/ES/RESULTADOS DE INVESTIGACIÓN PROYECTOS DESCIFRANDO VULNERABILIDADES EN EL MICROAMBIENTE TUMORAL DE LOS LINFOMAS DIFUSOS DE CELULAS B GRANDES
ISSN: 
2051-1426
Note: 
Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions.
Citation: 
Melchor-Sánchez, J. (Javier); García-Lacarte, M. (Marcos); Contreras-Grijalba, S. (Sara); et al. "Venetoclax improves CD20 immunotherapy in a mouse model of MYC/BCL2 double-expressor diffuse large B-cell lymphoma". Journal For Immunotherapy Of Cancer. 11 (2), 2023, e006113
Abstract
BackgroundApproximately one-third of diffuse large B cell lymphoma (DLBCL) patients exhibit co-expression of MYC and BCL2 (double-expressor lymphoma, DEL) and have a dismal prognosis. Targeted inhibition of the anti-apoptotic protein BCL2 with venetoclax (ABT-199) has been approved in multiple B-cell malignancies and is currently being investigated in clinical trials for DLBCL. Whether BCL2 anti-apoptotic function represents a multifaceted vulnerability for DEL-DLBCL, affecting both lymphoma B cells and T cells within the tumor microenvironment, remains to be elucidated.MethodsHere, we present novel genetically engineered mice that preclinically recapitulate DEL-DLBCL lymphomagenesis, and evaluate their sensitivity ex vivo and in vivo to the promising combination of venetoclax with anti-CD20-based standard immunotherapy.ResultsVenetoclax treatment demonstrated specific killing of MYC+/BCL2(+) lymphoma cells by licensing their intrinsically primed apoptosis, and showed previously unrecognized immunomodulatory activity by specifically enriching antigen-activated effector CD8 T cells infiltrating the tumors. Whereas DEL-DLBCL mice were refractory to venetoclax alone, inhibition of BCL2 significantly extended overall survival of mice that were simultaneously treated with a murine surrogate for anti-CD20 rituximab.ConclusionsThese results suggest that the combination of anti-CD20-based immunotherapy and BCL2 inhibition leads to cooperative immunomodulatory effects and improved preclinical responses, which may offer promising therapeutic opportunities for DEL-DLBCL patients.

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