Abstract B18: B-cell lymphoma patient-derived xenograft models: The road to personalized therapy
Authors: Zhang Leo , Pham Lan , Zhang Hui , Xie Jingmeng , Tao Wenjing , Bell Taylor , Chen Zhihong , Fang Bingliang , Wang Michael , Nomie Krystle 
Published: March 2017

Abstract
Lymphoma is the most common hematological malignancy, and B-cell lymphoma accounts for 85% of all lymphomas. The current overall cure rate for B-cell lymphoma is estimated at ~30%, even with the development and application of novel therapies, and the majority of patients relapse after treatment due to the development of drug resistance. The evaluation of novel drug targets using established B-cell lymphoma cell lines is limited by the inexact correlation between responsiveness observed in the cell line versus the patient sample. However, patient-derived xenograft (PDX) mouse models have been shown to recapitulate the diversity of growth, metastasis, and histopathology of the original tumor, overcoming the limitations of cell lines. Furthermore, recent studies have indicated that PDXs can recapitulate treatment responses of the parental tumor and can successfully choose a therapeutic target and regimen for the patient. We previously established a SCID-hu in vivo human primary mantle cell lymphoma (MCL) PDX model, the first human primary MCL animal model for biological and therapeutic research, and investigated the disease biology and potential novel human MCL therapies using this model. In this MCL PDX model, the engraftment and growth of patient MCL cells were dependent on the human bone marrow microenvironment supplied by an implanted human fetal bone chip. Our clinical information and reports show that numerous B-cell lymphoma subtypes involve bone marrow; therefore, we expanded our PDX model to include various B-cell lymphomas to study the clonal evolution of tumors and to evaluate novel therapies for the treatments of these diseases. PDX models (n=20) were established for multiple different types of B-cell lymphoma, including MCL (n=12), Burkitt's lymphoma (n=1), marginal zone lymphoma (n=2), follicular lymphoma (n=2), chronic lymphocytic leukemia (n=1) and diffuse large B-cell lymphoma (n=2). The engraftment rate was high at 95%, the tumor xenografts rapidly grew at 3-4 weeks/generation, and 68% of the tumor xenografts were passaged for multiple generations, even up to 14 generations. Further demonstrating the utility of this model to recapitulate the characteristics of the original patient tumor, the tumor xenograft cells migrated to the lymph nodes, spleen, bone marrow, and gastrointestinal tract of the host mice, mimicking the disease progression observed in humans, and H&E staining showed similar histological features between the original patient tumor and the tumor xenograft cells such as splenomegaly. To identify novel targeted treatments for these various lymphomas, we assessed the in vitro cell viability of MCL, DLBCL, and Burkitt's lymphoma cells from the patients and isolated from the PDXs of different generations. The responses to these agents were very similar between the PDXs and the original patient tumor, and the treatment responses were the same between different generations, showing that the PDX models recapitulate the drug response of the original tumor. Finally, in 34% of relapsed/refractory MCL patients who were treated with ibrutinib, transient lymphocytosis was observed, and this phenomenon was also observed in our MCL PDX mouse models treated with ibrutinib. Furthermore, the combination of ibrutinib and rituximab quenched lymphocytosis in the animal model, which provided the basis of using this combination in a clinical trial in which the MCL patients had an overall response rate of 88%. In conclusion, these data demonstrate the ability of PDX mouse models to successfully recapitulate and the characteristics of the original patient tumor as well as mimic the progression of the disease in vivo. In addition, the drug responses of the original patient tumor to various agents were similar to the responses of the tumor xenograft, demonstrating that these PDX models can be used as a way to personalize the treatment of numerous types of B-cell lymphomas.
Citation Format: Leo Zhang, Lan Pham, Hui Zhang, Jingmeng Xie, Wenjing Tao, Taylor Bell, Zhihong Chen, Bingliang Fang, Michael Wang, Krystle Nomie. B-cell lymphoma patient-derived xenograft models: The road to personalized therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B18.