title: Cytosine arabinoside promotes cytotoxic effect of T cells on leukemia cells mediated by bispecific antibody.
abstract: Chemotherapeutic drugs can enhance an immune response of the host against the tumor in addition to killing cancer cells by direct cytotoxicity. Therefore, the combination of chemotherapy and immunotherapy is a promising approach for eliminating tumors, particularly in advanced stages. A strategic medication is to use a bispecific antibody format that is capable of recruiting polyclonal T cells around antibody-target-expressing tumor cells. Recently, we have constructed a bispecific antibody, anti-CD3×anti-CD19, in a diabody configuration. In this study, we measured B7 family members B7.1 (CD80) and B7.2 (CD86) expressed on a CD19(+) human leukemia cell line, Nalm-6, stimulated by cytosine arabinoside (Ara-C). We found that a low concentration of Ara-C could upregulate CD80 expressed on CD19(+) Nalm-6 cells. The cytotoxicity of T lymphocytes against Nalm-6 cells in vitro and in vivo mediated by the anti-CD3×anti-CD19 diabody with or without a low dose of Ara-C was compared. The combination of the anti-CD3×anti-CD19 diabody and Ara-C showed the greatest effectiveness in enhancing the cytotoxicity of T cells against the tumor cells in vitro and in vivo. Activated T cells expressed higher levels of CD25 and CD69 and released more interleukin 2. Both perforin/granzyme B system and Fas/FasL pathway were involved in the diabody-induced T-cell cytotoxicity. Moreover, the activated T cells could upregulate ICAM-3 expression on Nalm-6 cells, and inhibition of LFA-1-ICAM-3 interaction impaired cytotoxicity of T cells. It was noted that Ara-C could upregulate CD80 expressed on two of five specimens of acute B lymphoblastic leukemia patient-derived cells. Cytotoxicity of T cells against these two patient-derived cells was enhanced in the presence of the anti-CD3×anti-CD19 diabody. These findings indicate that treatment strategy using both cytotoxic lymphocyte-based immunotherapy and chemotherapy may have synergistic effects.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: DongMei
authors.initials: D
authors.lastname: Fan
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.forename: RuiZan
authors.initials: R
authors.lastname: Shi
authors.forename: JunPing
authors.initials: J
authors.lastname: Cheng
authors.forename: ZhenZhen
authors.initials: Z
authors.lastname: Li
authors.forename: MengNan
authors.initials: M
authors.lastname: Zhang
authors.forename: JianXiang
authors.initials: J
authors.lastname: Wang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiong
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000378:metabolism*; D018122:B7-1 Antigen / Q000187:drug effects / Q000378:metabolism; D051940:B7-2 Antigen / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: D018033:Antibodies, Bispecific; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D003561:Cytarabine