CD30 targeting with brentuximab vedotin: a novel therapeutic approach to primary effusion lymphoma

Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
Blood (Impact Factor: 10.45). 07/2013; 122(7). DOI: 10.1182/blood-2013-01-481713
Source: PubMed


Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) characterized by short survival with current therapies, emphasizing the urgent need to develop new therapeutic approaches. Brentuximab vedotin (SGN-35) is an anti-CD30 monoclonal antibody (cAC10) conjugated by a protease-cleavable linker to a microtubule-disrupting agent monomethyl auristatin E (MMAE). Brentuximab vedotin is an effective treatment for relapsed CD30-expressing Classical Hodgkin and systemic anaplastic large cell lymphomas. Herein, we demonstrated that PEL cell lines and primary tumors express CD30 and thus may serve as potential targets for brentuximab vedotin therapy. In vitro treatment with brentuximab vedotin decreased cell proliferation, induced cell cycle arrest and triggered apoptosis of PEL cell lines. Furthermore, in vivo brentuximab vedotin promoted tumor regression and prolonged survival of mice bearing previously reported UM-PEL-1 tumors as well as UM-PEL-3 tumors derived from a newly established and characterized KSHV and EBV positive PEL cell line. Overall, our results demonstrate for the first time that brentuximab vedotin may serve as an effective therapy for PEL and provide strong preclinical indications for evaluation of brentuximab vedotin in clinical studies of PEL patients.

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    • "Other approaches outside traditional chemotherapy have been investigated, including the addition of anti-herpes therapy such as cidofovir (Halfdanarson et al., 2006) or the use of NF-κB inhibitors (Keller et al., 2006; An et al., 2004). Very recently, brentuximab vedotin (Bhatt et al., 2013a), which is an anti-CD30 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E, and a proteasome-HDAC inhibitor combination (Bhatt et al., 2013b) have been demonstrated to be effective against PEL. Although patients display response to therapy, remissions are often short-term and current chemotherapy approaches still result in poor outcome (Kaplan, 2012, 2013) warranting investigation of original therapeutic strategies for PEL. "
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    ABSTRACT: Introduction: Primary effusion lymphoma (PEL) is rare and aggressive B-cell non-Hodgkin's lymphoma that presents with malignant effusions without tumor masses. Kaposi's sarcoma-associated herpes virus/human herpes virus-8 is universally associated with the pathogenesis of PEL. It is generally resistant to chemotherapy with a short median survival of < 6 months. The optimal treatment for PEL is not well defined and there is a need to establish a standard therapy. Areas covered: This review summarizes the disease features, pathogenesis, diagnosis and current and new targeted treatments for PEL. A literature search on PubMed has been undertaken and the most relevant references have been considered. Expert opinion: Initiating or continuing combination antiretroviral therapy is recommended for HIV-infected PEL patients; however, there is no standard chemotherapy for PEL due to its low incidence and the lack of a large clinical study. PEL is resistant to conventional cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-like chemotherapy. Thus, therapeutic approaches that target aggressive and chemotherapy-resistant nature in PEL are considered for treatment. In the use of novel agents, further clinical studies on resistant hematological malignancy, such as multiple myeloma, would provide evidence for their clinical use.
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