Abstract #LB-138: A gene signature predicts sensitivity to the partial CD40 agonist, dacetuzumab (SGN-40), in patients with diffuse large B-cell lymphoma
Authors: Bart Burington, Ranjana Advani, Xiaoyan Shi, Peng Yue, Jeffrey Lau, Shang-Fan Yu, Thomas Januario, Sven de Vos, Stephen Ansell, Andres Forero-Torres, Allen Ebens, Nancy Whiting, David Dornan
Journal: Cancer Research (2009)

Background: Agonism of the CD40 pathway represents a unique therapeutic opportunity for the treatment of diffuse large B-cell lymphoma (DLBCL) since activation of CD40 promotes downregulation of the proto-oncogene BCL6 and, in a specific molecular context, may promote apoptosis and/or inhibition of proliferation in vitro. Dacetuzumab (SGN-40) is a humanized IgG1 monoclonal antibody that binds to CD40 and functions as a partial agonist and has shown single-agent activity in relapsed/refractory DLBCL in Phase I and II trials, with 36.8% (21/57) of patients showing tumor shrinkage. The identity of a specific molecular subtype of DLBCL that would benefit from CD40 agonism has heretofore not been described and could aid drug development decisions and inform potential drug combinations. Methods: A pharmacogenomic approach was employed in which 31 NHL cell lines were tested for sensitivity to dacetuzumab and for correlations with gene expression. Fifteen microarray probes were selected, using stepwise linear models for predicting dacetuzumab sensitivity. qRT-PCR probes were subsequently developed for archival tissue samples. Using patient samples from phase I and II clinical trials, a classifier based on qRT-PCR was developed for tumor size reduction of at least 10%, herein defined as dacetuzumab sensitive, using weighted k-nearest-neighbors, with weights for the 15 probes determined using penalized regression (GLMNET). Model parameters were determined by cross-validation and robust p-values were computed via permutation tests. Results and Conclusion: Gene expression profiling of NHL cell lines identified that dacetuzumab activity in vitro correlated with a gene signature that was representative of minimal CD40 pathway activation. This was in contrast to dacetuzumab resistant cell lines that displayed a gene expression signature that was representative of an activated CD40 pathway. Therefore, dacetuzumab appears to elicit its apoptotic properties through activation of CD40 signaling in NHL cell lines not previously exposed to CD40L signaling. When applying the selected signature probes to clinical cases treated in clinical trials, 10 out of 15 (67%) who were marker positive were sensitive and 21 out of 24 (88%) who were marker negative were not sensitive to dacetuzumab. The overall accuracy for predicting sensitivity to dacetuzumab was 80% (one-sided P=0.004, by permutation test). Of the 15 genes contributing to the multivariate signature, CD22 was the most strongly upregulated in specimens from dacetuzumab sensitive patients (P=0.07), while EPDR1 was the most strongly downregulated (P=0.10). These data suggest that agonism of CD40 pathway may be a promising therapeutic approach and can be enriched by a novel gene signature that provides unique perspectives regarding the future development of CD40 targeted therapies and potential drug combinations in DLBCL.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-138.