B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy

Leo Zhang, Krystle Nomie, Hui Zhang, Taylor Bell, Lan Pham, Sabah Kadri, Jeremy Segal, Shaoying Li, Shouhao Zhou, David Santos, Shawana Richard, Shruti Sharma, Wendy Chen, Onyekachukwu Oriabure, Yang Liu, Shengjian Huang, Hui Guo, Zhihong Chen, Wenjing Tao, Carrie Li, Jack Wang, Bingliang Fang, Jacqueline Wang, Lei Li, Maria Badillo, Makhdum Ahmed, Selvi Thirumurthi, Steven Y. Huang, Yiping Shao, Laura Lam, Qing Yi, Y. Lynn Wang, Michael Wang

Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma PDX (patient-derived xenograft) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options. We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt's lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice. We subjected the PDX models to histopathological and phenotypical examination, sequencing, and drug efficacy analysis. Primary and acquired resistance to ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, were investigated to elucidate the mechanisms underlying ibrutinib resistance and to identify drug treatments to overcome resistance. The PDXs maintained the same biological, histopathological, and immunophenotypical features, retained similar genetic mutations and produced comparable drug responses with the original patient tumors. In the acquired ibrutinib-resistant PDXs, PLC-γ2, p65, and Src were down-regulated; however, a PI3K signaling pathway member was up-regulated. Inactivation of the PI3K pathway with the inhibitor idelalisib in combination with ibrutinib significantly inhibited the growth of the ibrutinib-resistant tumors. Furthermore, we used a PDX model derived from a clinically ibrutinib-relapsed patient to evaluate various therapeutic choices, ultimately eliminating the tumor cells in the patient's peripheral blood. Our results demonstrate that the B-cell lymphoma PDX model is an effective system to predict and personalize therapies and address therapeutic resistance in B-cell lymphoma patients.