CD40 Pathway Activation Status Predicts Response to CD40 Targeted Therapy in Diffuse Large b-Cell Lymphoma.

Abstract 2721

Poster Board II-697

The role of the CD40 pathway in B-cell cancers is rather enigmatic due to having polar opposite roles in tumor biology. Stimulation of the CD40 receptor can reduce cell viability of NHL cell lines and xenograft tumor models, whereas, in sharp contrast, constitutive CD40 stimulation can actually promote proliferation of NHL cell lines, as well as drive lymphomagenesis and transformation of primary B-cells. Therefore, targeting the CD40 pathway has been challenging due to a knowledge gap in understanding the factors that may dictate a pro- or anti-tumor role. To address this directly, we employed a large panel of NHL cell lines and xenografts models to simulate a patient population and to define the molecular parameters to test in the context of clinical trials. Using baseline gene expression profiling, we found that the in vitro activity of an antibody that stimulates the CD40 pathway, Dacetuzumab (SGN-40), correlated strikingly with a transcriptional profile that was representative of an inactive CD40 pathway. Resistant cells, on the other hand, displayed a transcriptional profile indicative of an activated CD40 pathway. Consistent with these observations, constitutive phosphorylation of ERK, a node downstream of CD40 signaling, was present predominantly in cell lines that were resistant to Dacetuzumab. Fifteen genes, based on their association with in vitro activity and their biology as components of the CD40 network, were selected as a classifier from these pre-clinical data and independently tested in a panel of cell lines and xenografts models. Testing the selected gene classifier by qRT-PCR from baseline fixed tumor tissue of 39 patients treated with Dacetuzumab in phase I and II clinical trials revealed the ability to predict sensitivity in patients, as determined by tumor shrinkage >10%, with an overall accuracy of 80%. Consistent with the observed tumor shrinkage, the classifier positive, predicted to respond to Dacetuzumab, patients also exhibited a prolonged progression free survival (PFS) compared to classifier negative patients, predicted not to respond to Dacetuzumab (HR = 0.23, p = 0.001). Finally, using a novel microarray approach to genome-wide expression profiling on fixed tumor tissue revealed that CD40 pathway activation was indeed an important predictor of response. Overall, these data suggest that sensitivity to Dacetuzumab can be predicted by pre-determining the CD40 pathway activation status of tumors.