Abstract
Non-Hodgkin lymphomas (NHLs) account for 4% of all malignancies. 5-year survival rate increased to 50% with new treatment modalities, however there is need for new effective treatment for the more aggressive, relapsing forms. Recently, CTLA4-FasL, that can bind to B7 and Fas receptor (Fas), was shown to induce robust apoptosis of cell lines originating from B cell lymphomas expressing both B7 and Fas, by activating pro-apoptotic signals in parallel to abrogating anti-apoptotic ones. The present study focuses on the unique properties of CTLA4-FasL as a potent apoptosis inducer of malignant cells in-vitro and in a xenograft model. CTLA4-FasL was found to naturally form a stable homo-hexamer. CTLA4-FasL induces robust apoptosis of a large variety of malignant cells while relatively sparing non-malignant ones, being more efficient when both receptors (B7 and Fas) are expressed on target cells. Even in non-B7 expressing cells, CTLA4-FasL exhibited better apoptotic activity than its parts, alone or in combination, however, only in B7 expressing cells apoptosis occurs at low concentrations and CTLA4-FasL induces activation of apoptotic signals and reduces anti-apoptotic ones. Importantly, CTLA4-FasL efficiently inhibited the growth of human B cell lineage tumors in a xenograft model, by provoking tumor cells' apoptosis. Thus, CTLA4-FasL, a natural homo-hexamer protein, induces robust apoptosis of malignant cells, in-vitro and in-vivo. In B-cell lymphoma, its potency stems from the combination of its synergistic effect of activating the caspases while abrogating the anti-apoptotic signaling, with its unique hexameric structure, making CTLA4-FasL a promising candidate for aggressive B cell lymphomas treatment.
Original language | American English |
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Article number | 64 |
Journal | Journal of Hematology and Oncology |
Volume | 7 |
Issue number | 1 |
DOIs | |
State | Published - 17 Sep 2014 |
Externally published | Yes |
Bibliographical note
Funding Information:Amsili Shira, Kobi Tzdaka, Fanny Szafer and Noam Shani are employed by KAHR Medical LTD that owns the CTLA4-FasL patent. NS is the CEO. Per Edebrink and Mari-Anne Rauvola are employed by Cobra Biologics that produces CTLA4-FasL. Michal Dranitzki Elhalel has a research grant from KAHR Medical LTD, and consultant fees.
Publisher Copyright:
© 2014 Aronin et al.; licensee BioMed Central Ltd.