Venetoclax Improves CD20 Immunotherapy in a Mouse Model of MYC/BCL2 Double-expressor Diffuse Large B-cell Lymphoma

Overview

Journal J Immunother Cancer

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2023 Feb 28

PMID 36854569

Authors

Javier Melchor

Marcos Garcia-Lacarte

Sara C Grijalba

Adrian Arnaiz-Leche

Marien Pascual

Carlos Panizo

Oscar Blanco

Victor Segura

Francisco J Novo

Juan Garcia Valero

Patricia Perez-Galan

Jose A Martinez-Climent

Sergio Roa

Affiliations

Soon will be listed here.

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.

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