Angioimmunoblastic T-cell lymphoma: Characterization of clonal T and B cells and a patient-derived xenograft study of coexisting T- and B-cell proliferation.

Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive lymphoma with a poor prognosis. AITL is associated with Epstein-Barr virus (EBV)-positive B cells in most cases, suggesting a possible role for the virus in the pathobiology of AITL. Cell lines from AITL patients do not exist and models of human AITL are needed. We aim to establish such a model and use it for preclinical therapeutic evaluation. Methods: Primary lymph node tissue from an AITL patient was used for tumor cell isolation and injection to NSG mice. The established patient-derived xenograft (PDX) model was characterized by immunophenotyping, whole-exome sequencing (WES), and T/B-cell receptor gene rearrangement studies. In vivo AITL PDX trials were performed with elotuzumab, romidepsin, and rituximab. Results: An AITL PDX mouse model that includes a coexisting EBV+ B-cell proliferation was established. We confirmed clonal identity of the engrafted T cells with the primary T-lymphoma cells. WES on DNA from xenografted sorted T and B cells identified eight and three mutations previously reported in the COSMIC database, respectively. Primary tumor cells could be passaged serially in NSG mice with an increasing percentage of monoclonal B cells that mimic the human condition in which the clonal B-cell component in some cases may mask an underling T-cell lymphoma. In this PDX mouse study, single agent elotuzumab or rituximab significantly improved mice survival. Survival was further improved when elotuzumab or romidepsin was combined with rituximab. Conclusion: To our knowledge, this is the first molecular characterization of AITL model coexisting with associated EBV+ B cells, and use of such a PDX model for therapeutic evaluation of agents targeting both malignant T cells and B cells simultaneously.