title: Mesenchymal stromal cells as vehicles of tetravalent bispecific Tandab (CD3/CD19) for the treatment of B cell lymphoma combined with IDO pathway inhibitor D-1-methyl-tryptophan.
abstract: Although blinatumomab, a bispecific T cell engaging antibody, exhibits high clinical response rates in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL) and B cell non-Hodgkin's lymphoma (B-NHL), it still has some limitations because of its short half-life. Mesenchymal stromal cells (MSCs) represent an attractive approach for delivery of therapeutic agents to cancer sites owing to their tropism towards tumors, but their immunosuppression capabilities, especially induced by indoleamine 2,3-dioxygenase (IDO), should also be taken into consideration.
  
  
  
  Human umbilical cord-derived MSCs (UC-MSCs) were genetically modified to secrete Tandab (CD3/CD19), a tetravalent bispecific tandem diabody with two binding sites for CD3 and two for CD19. The tropism of MSCs towards Raji cells in vitro was determined by migration assays, and the homing property of MSCs in vivo was analyzed with firefly luciferase-labeled MSCs (MSC-Luc) by bioluminescent imaging (BLI). The cytotoxicity of T cells induced by MSC-secreting Tandab (CD3/CD19) was detected in vitro and in vivo in combination with D-1-methyl-tryptophan (D-1MT), an IDO pathway inhibitor.
  
  
  
  The purified Tandab (CD3/CD19) was functional with high-binding capability both for CD3-positive cells and CD19-positive cells and was able to induce specific lysis of CD19-positive cell lines (Raji, Daudi, and BJAB) in the presence of T cells. Additionally, results from co-culture killing experiments demonstrated that Tandab (CD3/CD19) secreted from MSCs was also effective. Then, we confirmed that D-1MT could enhance the cytotoxicity of T cells triggered by MSC-Tandab through reversing T cell anergy with down-regulation of CD98 and Jumonji and restoring the proliferation capacity of T cells. Furthermore, MSC-Luc could selectively migrate to tumor site in a BALB/c nude mouse model with Raji cells. And mice injected with MSC-Tandab in combination with D-1MT significantly inhibited the tumor growth.
  
  
  
  These results suggest that UC-MSCs releasing Tandab (CD3/CD19) is an efficient therapeutic tool for the treatment of B cell lymphoma when combined with D-1MT.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020, People's Republic of China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020, People's Republic of China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020, People's Republic of China.
authors.forename: Leisheng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020, People's Republic of China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Fan
authors.affiliation: Central Hospital of Karamay, Karamay, Xinjiang, 834000, People's Republic of China.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020, People's Republic of China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Central Hospital of Karamay, Karamay, Xinjiang, 834000, People's Republic of China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, 300020, People's Republic of China. dsxiong@ihcams.ac.cn.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiong
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity; D018941:Antigens, CD19 / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020014:K562 Cells; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D057127:Single-Chain Antibodies; D013601:T-Lymphocytes / Q000276:immunology; D014364:Tryptophan / Q000031:analogs & derivatives
chemical_list: D018033:Antibodies, Bispecific; D000912:Antibodies, Neoplasm; D018941:Antigens, CD19; D017252:CD3 Complex; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D057127:Single-Chain Antibodies; C028129:tryptophan methyl ester; D014364:Tryptophan
keywords: B cell lymphoma; Bispecific antibodies; CD19; CD3; D-1-methyl-tryptophan; MSCs