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Abstract

Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell non-Hodgkin lymphoma (B-NHL). The BCL-2 small-molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by radiotherapy increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation. We tested B-NHL responses to venetoclax combined with either external beam radiotherapy or radioimmunotherapy (RIT), which joins the selectivity of antibody targeting with the effectiveness of irradiation. We first tested cytotoxicity of cesium-137 irradiation plus venetoclax in 14 B-NHL cell lines representing five lymphoma subtypes. Combination treatment synergistically increased cell death in 10 of 14 lines. Lack of synergy was predicted by resistance to single-agent venetoclax and high BCL-XL expression. We then assessed the efficacy of external beam radiotherapy plus venetoclax in murine xenograft models of mantle cell (MCL), germinal-center diffuse large B-cell (GCB-DLBCL), and activated B-cell (ABC-DLBCL) lymphomas. In each model, external beam radiotherapy plus venetoclax synergistically increased mouse survival time, curing up to 10%. We finally combined venetoclax treatment of MCL and ABC-DLBCL xenografts with a pretargeted RIT (PRIT) system directed against the CD20 antigen. Optimal dosing of PRIT plus venetoclax cured 100% of mice with no detectable toxicity. Venetoclax combined with radiotherapy may be a promising treatment for a wide range of lymphomas

Author information

O'Steen S1, Green DJ2,3, Gopal AK2,3, Orozco JJ2,3, Kenoyer AL2, Lin Y2, Wilbur DS4, Hamlin DK4, Fisher DR5, Hylarides MD2, Gooley TA2, Waltman A6, Till BG2,3, Press OW2,3,7.

1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. sosteen@fredhutch.org.2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.3Department of Medicine, University of Washington, Seattle, Washington.4Department of Radiation Oncology, University of Washington, Seattle, Washington.5Versant Physics, Richland, Washington.6University of Chicago, Chicago, Illinois.7Department of Bioengineering, University of Washington, Seattle, Washington.