Prevention of Human Lymphoproliferative Tumor Formation in Ovarian Cancer Patient-Derived Xenografts

Abstract

Interest in preclinical drug development for ovarian cancer has stimulated development of patient-derived xenograft (PDX) or tumorgraft models. However, the unintended formation of human lymphoma in severe combined immunodeficiency (SCID) mice from Epstein-Barr virus (EBV)–infected human lymphocytes can be problematic. In this study, we have characterized ovarian cancer PDXs which developed human lymphomas and explore methods to suppress lymphoproliferative growth. Fresh human ovarian tumors from 568 patients were transplanted intraperitoneally in SCID mice. A subset of PDX models demonstrated atypical patterns of dissemination with mediastinal masses, hepatosplenomegaly, and CD45-positive lymphoblastic atypia without ovarian tumor engraftment. Expression of human CD20 but not CD3 supported a B-cell lineage, and EBV genomes were detected in all lymphoproliferative tumors. Immunophenotyping confirmed monoclonal gene rearrangements consistent with B-cell lymphoma, and global gene expression patterns correlated well with other human lymphomas. The ability of rituximab, an anti-CD20 antibody, to suppress human lymphoproliferation from a patient's ovarian tumor in SCID mice and prevent growth of an established lymphoma led to a practice change with a goal to reduce the incidence of lymphomas. A single dose of rituximab during the primary tumor heterotransplantation process reduced the incidence of CD45-positive cells in subsequent PDX lines from 86.3% (n = 117 without rituximab) to 5.6% (n = 160 with rituximab), and the lymphoma rate declined from 11.1% to 1.88%. Taken together, investigators utilizing PDX models for research should routinely monitor for lymphoproliferative tumors and consider implementing methods to suppress their growth.

Hepatocellular Carcinoma Xenografts Established From Needle Biopsies Preserve the Characteristics of the Originating Tumors

“…D). These results suggest the development of lymphomas in the xenografts as has been reported in PDX studies of various cancers . These three PDX tumors stained positive for the human B‐cell marker CD20 (Fig.…”

“…The histologic appearance of lymphocytes, strong positivity for the human B‐cell marker CD20, transcriptional up‐regulation of immune cell signatures, loss of expression of the HCC‐specific somatic mutations, and distinct CNA profiles suggest that human B‐cell lymphomas were formed in these PDX models. This phenomenon has been described for PDX models derived from a number of human cancer tissues . It has been reported that treatment with rituximab, an anti‐CD20 monoclonal antibody, prevented lymphomatous outgrowth in early passage ovarian xenografts .…”

Tumor characteristics associated with engraftment of patient‐derived non–small cell lung cancer xenografts in immunocompromised mice

“…2,33 The proliferation of EBV-positive B cells in tumor samples also has been reported to result in the formation of human B-cell lymphomas and the failure of PDX growth in specimens from patients with several types of cancer, including lung cancer. 35 In addition to lymphoma, immune cells present within tumor samples and cotransplanted into the subcutis of NSG mice can induce graft-versushost disease before successful primary tumor engraftment, 30 or coexist with tumor cells in early passages of PDXs. 35 In addition to lymphoma, immune cells present within tumor samples and cotransplanted into the subcutis of NSG mice can induce graft-versushost disease before successful primary tumor engraftment, 30 or coexist with tumor cells in early passages of PDXs.…”

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

“…To some extent, mouse stromal cells in the TME share common features with matched human cells in parental tumors, but the exact impact of murine stroma on human cancer cells in PDX models remains unknown. Third, the engraftment of a PDX can cause lymphoma but not the expected tumors in host mice if the donor patient has a history of Epstein Barr virus infection …”