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

Abstract

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.

Studying the role of BCL2 and MYC in the pathogenesis of diffuse large B cell lymphoma

“…4. Optimization of novel ex vivo 3D murine lymphoma modelsTumor microenvironment (TME) plays an essential role in the progression and response of DLBCL to immunotherapy, and using targeted inhibitors, as we show here for venetoclax, may cooperate with standard therapies to reinvigorate tumor-infiltrating T-cells, promoting long-term tumor control and improving overall survival Kohlhapp et al, 2020;Melchor et al, 2023). However, characterizing TME responses to immunotherapy combinations mostly relays on using in vivo studies with immunocompetent animal models, as alternative in vitro models recapitulating the complex interactions between tumor cells and TME are still under development.…”

“…Checked fastq files were mapped to mouse mm10 genome using STAR 2.5.2b with default parameters, annotated with GENCODE vM25 and quantified with featureCounts c1.6.0 using read counts of exonic gene regions. Files have been deposited in NCBI Gene Expression Omnibus and are accessible through GEO SuperSeries accession number GSE197693 (Melchor et al, 2023).…”