Research ArticleCancer

CD40 Pathway Activation Status Predicts Response to CD40 Therapy in Diffuse Large B Cell Lymphoma

Science Translational Medicine  16 Mar 2011:
Vol. 3, Issue 74, pp. 74ra22
DOI: 10.1126/scitranslmed.3001620

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Matching Treatment to Tumor

If physicians could predict the future, it would take the guess work out of designing the right treatment regimen for every patient’s cancer. The results presented by Burington et al. move us closer to clearing the crystal ball for diffuse large B cell lymphomas, a common type of non-Hodgkin’s lymphoma in which a cell surface receptor, CD40, presents a seemingly attractive target for therapy. Although stimulation of CD40 by ligand binding can cause apoptosis of B cells—a trait that one would predict to be desirable for a B cell lymphoma drug—it can also induce undesirable proliferation of some lymphoma cells. This murky paradox makes it unclear when to prescribe dacetuzumab, a CD40-targeted therapeutic monoclonal antibody. The authors have now identified a 15-gene expression signature that signals the biochemical status of a lymphoma, thus clarifying whether it can be subdued by anti-CD40 therapy.

The authors collected an array of cell lines derived from non-Hodgkin’s lymphomas that show a range of sensitivity to anti-CD40 therapy. By assessing gene expression before and after CD40 stimulation and creating a score that reflected CD40 pathway activation, Burington et al. found that cell lines with higher baseline activation of the CD40 pathway tended to be unresponsive to anti-CD40 stimulation. The researchers then identified a group of 15 active genes whose expression in formalin-fixed tissue (as would be obtained from patients) correctly predicted susceptibility to anti-CD40 treatment 77% of the time, a result verified in another set of cells lines and by quantitative polymerase chain reaction (PCR).

Next, in a real-world test of the utility of this 15-gene predictor, tumor tissue samples from 39 patients who had been treated with dacetuzumab were scored for CD40 pathway activation with the new gene signature. A large majority (88%) of the patients predicted by the gene signature to be resistant to therapy in fact did not respond to therapy, showing a median progression-free survival of 40 days; 67% of those predicted to respond to dacetuzumab did so, with median progression-free survival extended to 169 days.

These results encourage further testing in a prospective clinical trial designed to examine the ability of the 15-gene signature to predict which lymphoma patients will benefit from dacetuzumab treatment. If this index proves useful, it can be added to the catalog of prognostic tools at the service of the oncologist as they match drug to patient—without the need of a crystal ball.


  • * These authors contributed equally to this work.

  • Citation: B. Burington, P. Yue, X. Shi, R. Advani, J. T. Lau, J. Tan, S. Stinson, J. Stinson, T. Januario, S. de Vos, S. Ansell, A. Forero-Torres, G. Fedorowicz, T. T. C. Yang, K. Elkins, C. Du, S. Mohan, N. Yu, Z. Modrusan, S. Seshagiri, S.-F. Yu, A. Pandita, H. Koeppen, D. French, A. G. Polson, R. Offringa, N. Whiting, A. Ebens, D. Dornan, CD40 Pathway Activation Status Predicts Response to CD40 Therapy in Diffuse Large B Cell Lymphoma. Sci. Transl. Med. 3, 74ra22 (2011).