Case-control Indian buffet process identifies biomarkers of response to Codrituzumab

Melanie F Pradier, Bernhard Reis, Lori Jukofsky, Francesca Milletti, Toshihiko Ohtomo, Fernando Perez-Cruz, Oscar Puig, Melanie F Pradier, Bernhard Reis, Lori Jukofsky, Francesca Milletti, Toshihiko Ohtomo, Fernando Perez-Cruz, Oscar Puig

Abstract

Background: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3), which is expressed in hepatocellular carcinoma (HCC), was tested in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. Biomarker analysis was performed to identify a responder population that benefits from treatment.

Methods: A novel statistical method based on the Indian buffet process (IBP) was used to identify biomarkers predictive of response to treatment with Codrituzumab. The IBP is a novel method that allows flexibility in analysis design, and which is sensitive to slight, but meaningful between-group differences in biomarkers in very complex datasets RESULTS: The IBP model identified several subpopulations of patients having defined biomarker values. Tumor necrosis and viable cell content in the tumor were identified as prognostic markers of disease progression, as were the well-known HCC prognostic markers of disease progression, alpha-fetoprotein and Glypican-3 expression. Predictive markers of treatment response included natural killer (NK) cell surface markers and parameters influencing NK cell activity, all related to the mechanism of action of this drug CONCLUSIONS: The Indian buffet process can be effectively used to detect statistically significant signals with high sensitivity in complex and noisy biological data TRIAL REGISTRATION: NCT01507168 , January 6, 2012.

Keywords: Codrituzumab; Indian buffet process; Natural killer cells.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by institutional review boards of participating centers and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. NCT01507168 trial was approved by the institutional IRBs from all participating centers, and all patients received informed consent; consent from study participants was written; it has already been published with a previous study in [8]. Our study adheres to CONSORT guidelines for reporting clinical trials. A full list of all ethics commitees, participant centers, and additional details regarding this trial can be retrieved at: https://clinicaltrials.gov.

Consent for publication

Not applicable.

Competing interests

Roche employment and stock for authors BR, LJ, FM, and OP. Author TO was employed by Chugai.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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