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.
