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

• Published in: Journal for immunotherapy of cancer Vol. 11; no. 2; p. e006113
• Main Authors: Melchor, Javier, Garcia-Lacarte, Marcos, Grijalba, Sara C., Arnaiz-Leché, Adrián, Pascual, Marién, Panizo, Carlos, Blanco, Oscar, Segura, Victor, Novo, Francisco J., Valero, Juan Garcia, Pérez-Galán, Patricia, Martinez-Climent, Jose A., Roa, Sergio
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.02.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Animals; Antibodies; B-lymphocytes; Basic Tumor Immunology; Blood cancer; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cancer; CD4-CD8 ratio; Cloning; Disease Models, Animal; drug evaluation, preclinical; Flow cytometry; Gene expression; hematologic neoplasms; Immunization; Immunotherapy; Immunotherapy - methods; Lymphocytes; Lymphoma; Lymphoma, Large B-Cell, Diffuse - drug therapy; Mice; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Tumor Microenvironment; hematologic neoplasms; B-lymphocytes; drug evaluation, preclinical; CD4-CD8 ratio; immunotherapy
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2022-006113

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.