title: Human umbilical cord mesenchymal stem cells as vehicles of CD20-specific TRAIL fusion protein delivery: a double-target therapy against non-Hodgkin's lymphoma.
abstract: Mesenchymal stem cells (MSCs) are an attractive candidate for cell-based therapy. We have designed a promising double-target therapeutic system for non-Hodgkin's lymphoma (NHL) therapy. The system is based on MSC homing capacity and scFvCD20 antigen-restriction to NHL. In this system, a novel secreted fusion protein scFvCD20-sTRAIL, which contains a CD20-specific single chain Fv antibody fragment (scFv) and a soluble tumor necrosis factor related apoptosis-inducing ligand (sTRAIL, aa residues 114-281) with an isoleucine zipper (ISZ) added to the N-terminal (ISZ-sTRAIL), was expressed in human umbilical cord derived mesenchymal stem cells (HUMSCs). When compared with ISZ-sTRAIL protein, the scFvCD20-sTRAIL fusion protein demonstrated a potent inhibition of cell proliferation in CD20-positive BJAB cells, moderate inhibition in Raji cells, weak inhibition in CD20-negative Jurkat cells, and no effect on normal human peripheral blood mononuclear cells (PBMCs). The scFvCD20-sTRAIL fusion protein also caused significant increase of cellular apoptosis through both extrinsic and intrinsic apoptosis signaling pathways. Using a NOD/SCID mouse subcutaneous BJAB lymphoma xenograft model, the tropism of the firefly luciferase (fLuc) labeled MSC was monitored by bioluminescent imaging (BLI) for fLuc activity. Our study indicated that HUMSCs selectively migrated to the tumor site after 24 h of intravenous injection and mice injected with the MSC.scFvCD20-sTRAIL significantly inhibited the tumor growth when compared with those treated with MSC.ISZ-sTRAIL. The treatment was tolerated well in mice, as no obvious toxicities were observed. Our study has suggested that scFvCD20-sTRAIL secreting HUMSCs is a novel and efficient therapeutic approach for the treatment of non-Hodgkin's lymphoma.
authors.affiliation: State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, PR China.
authors.forename: Cihui
authors.initials: C
authors.lastname: Yan
authors.forename: Shuangjing
authors.initials: S
authors.lastname: Li
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Li
authors.forename: Hongwei
authors.initials: H
authors.lastname: Peng
authors.forename: Xiangfei
authors.initials: X
authors.lastname: Yuan
authors.forename: Linlin
authors.initials: L
authors.lastname: Jiang
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Fan
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiong
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D016086:Lentivirus / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics / Q000628:therapy*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology*
chemical_list: D018951:Antigens, CD20; D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human