Scientific publications

Venetoclax improves CD20 immunotherapy in a mouse model of MYC/BCL2 double-expressor diffuse large B-cell lymphoma

Feb 11, 2023 | Magazine: Journal for Inmunotherapy of Cancer

Javier Melchor 1 2, Marcos Garcia-Lacarte 1 2 3, Sara C Grijalba 1 3, Adrián Arnaiz-Leché 1 3, Marién Pascual 2, Carlos Panizo 3 4 5, Oscar Blanco 6, Victor Segura 7 8, Francisco J Novo 1 3, Juan Garcia Valero 9 10, Patricia Pérez-Galán 9 10, Jose A Martinez-Climent 2 3 10, Sergio Roa 11 2 3 10


Abstract

Background: Approximately 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.

Methods: Here, 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.

Results: Venetoclax 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.

Conclusions: These 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.

CITA DEL ARTÏCULO J Immunother Cancer. 2023 Feb;11(2):e006113. doi: 10.1136/jitc-2022-006113.