Edi Levi

A Murine Xenograft Model for Human CD30+ Anaplastic Large Cell Lymphoma: Successful Growth Inhibition with an Anti-CD30 Antibody (HeFi-1)

To develop a model for the biology and treatment of CD30+ anaplastic large cell lymphoma (ALCL), we transplanted leukemic tumor cells from a 22-month-old girl with multiple relapsed ALCL. Tumor cells were inoculated intraperitoneally into a 4-week-old SCID/bg mouse and produced a disseminated tumor within 8 weeks; this tumor was serially transplanted by subcutaneous injections to other mice. Morphology, immunohistochemistry, and molecular genetics which demonstrated the NPM-ALK fusion protein, resulting from the t(2;5)(p23;q35), confirmed the identity of the xenograft with the original tumor. The tumor produced transcripts for interleukin-1alpha, tumor necrosis factor-alpha, and interferon-gamma which could explain the patients B-symptoms. Treatment of mice with monoclonal antibody (HeFi-1) which activates CD30 antigen administered on day 1 after tumor transplantation prevented tumor growth. Treatment with HeFi-1 after tumors had reached a 0.2 cm(3) volume caused tumor growth arrest and prevention of tumor dissemination. We conclude that transplantation of CD30+ ALCL to SCID/bg mice may provide a valuable model for the study of the biology and design of treatment modalities for CD30+ ALCL.

Fascin expression in CD30-positive cutaneous lymphoproliferative disorders

Background: CD30‐positive cutaneous lymphoproliferative disorders (LPD) represent a spectrum of diseases ranging from low‐grade (lymphomatoid papulosis; LyP) to high‐grade (pleomorphic and anaplastic large‐cell lymphoma; PTL, ALCL) with overlapping morphologic and immunophenotypic features. The common phenotypic hallmark is the expression of CD30‐antigen by the tumor cells which morphologically resemble Reed–Sternberg cells. Although LyP is a non‐fatal recurring disorder, it is associated with systemic lymphomas including Hodgkins lymphoma (HL), mycosis fungoides (MF) and ALCL in 5–20% of the cases. Currently there is no marker to predict the development of systemic lymphomas in patients with LyP. Fascin, an actin bundling protein, has recently been shown to be a unique marker found in almost 100% of classical HL.

Progression of Lymphomatoid Papulosis to Systemic Lymphoma Is Associated with Escape from Growth Inhibition by Transforming Growth Factor‐β and CD30 Ligand

Abstract: Our objective is to understand the mechanism of progression of lymphomatoid papulosis (LyP) to CD30+ systemic lymphoma. LyP lesions appear in recurrent crops that regress, only to reappear at a later date in the same or different locations. About 10% of patients develop systemic lymphoma. Because transforming growth factor‐beta (TGF‐β) and CD30 ligand inhibit the growth of normal lymphocytes and can be detected in regressing lesions of LyP, we tested the effect of these cytokines on cell lines clonally derived from LyP in the progression to systemic lymphoma. TGF‐β failed to inhibit the growth of lymphoma cells from advanced disease due to mutations of the TGF‐β receptor complex that prevented binding of the ligand to tumor cells. A CD30 ligand agonist antibody caused proliferation of tumor cells from one patient and had no effect on tumor cells of another. In contrast, a Fas agonist antibody caused significant growth inhibition of all cell lines. The results suggest that progression of LyP to lymphoma is associated with escape of lymphoma cells from growth regulation by TGF‐β and CD30 ligand.