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

Melchor, J; Garcia-Lacarte, M; Grijalba, SC; Arnaiz-Leché, A; Pascual, M; Panizo, C; Blanco, O; Segura, V; Novo, FJ; Valero, JG; Pérez-Galán, P; Martinez-Climent, JA; Roa, S

Journal article

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

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.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Melchor, J., Garcia-Lacarte, M., Grijalba, S. C., Arnaiz-Leché, A., Pascual, M., Panizo, C., Blanco, O., Segura, V., Novo, F. J., Valero, J. G., Pérez-Galán, P., Martinez-Climent, J. A., & Roa, S. (2023). 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).

MLA Style

Melchor, J, 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, vol. 11, no. 2, 2023.

Chicago Style

Melchor, J, M Garcia-Lacarte, SC Grijalba, et al. 2023. “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).
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