Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 11, Issue 2, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2022-006113
Keywords
B-lymphocytes; CD4-CD8 ratio; hematologic neoplasms; immunotherapy; drug evaluation; preclinical
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This study demonstrates that venetoclax can selectively kill MYC+/BCL2(+) lymphoma cells and enhance the infiltration of antigen-activated effector CD8 T cells in the tumor microenvironment, improving the therapeutic response. The combination of anti-CD20-based immunotherapy and BCL2 inhibition shows cooperative immunomodulatory effects and offers promising therapeutic opportunities for DEL-DLBCL patients.
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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