Effective tumor vaccines generated by in vitro modification of tumor cells with cytokines and bispecific monoclonal antibodies

Abstract

Antitumor immune responses are mediated primarily by T cells. Downregulation of the major histocompatibility complex (MHC) and the molecules that costimulate the immune response is associated with defective signaling by tumor cells for T-cell activation. In vitro treatment with a combination of cytokines significantly increased the expression of MHC class I and adhesion molecules on tumor cell surfaces. When tumor cells were first incubated with a bispecific monoclonal antibody that binds antigen on tumor cells to CD28 on T cells, the modified tumor cells become immunogenic and are able to stimulate naive T cells, generating tumor-specific cytotoxic T cells in vitro. Immunization with the modified tumor cells elicits an immune response mediated by CD8+ T cells. This response protected against a challenge with parental tumor cells and cured established tumors. The approach was effective in both low immunogenic and nonimmunogenic tumor model systems. Modification of tumor cells with this two-step procedure may provide a strategy for development of tumor vaccines that is effective for cancer immunotherapy.

Enhancement of immunogenicity of tumor cells by cotransfection with genes encoding antisense insulin-like growth factor-1 and B7.1 molecules

“…Highly tumorigenic clones were established by in vivo selection and used in this study. 24 The SMCC-1 cell line was established from a chemically induced colon carcinoma originating in a C57BL/6 mouse. Cells derived from this cancer grow and form s.c. nodes in syngeneic animals.…”

“…The cytotoxicity of CTLs generated in vitro by stimulating naive spleen cells or spleens freshly prepared from the immunized mice was determined in a standard 4-hour 51 Cr release assay. 24 For the CTL adoptive transfer experiments, 6-to 8-week-old C57BL/6 mice in groups of five each were injected s.c. with 1 ϫ 10 6 SMCC-1 or hepa 1-6 cells. After 2 weeks, 1 ϫ 10 7 CTLs generated by priming naive spleen cells in vitro with double transfectants or spleen cells obtained from mice immunized with double transfectants were injected intravenously (i.v.)…”

“…Both grow rapidly, forming subcutaneous (s.c.) tumors. 24,25 The lack of both MHC class I and B7 molecules on cell surfaces and the failure to induce host immune responses when transfected with genes encoding either antisense IGF-1 or the B7.1 molecule make the two cell lines unique in vivo tumor model systems, and both are well-suited for experimental immunotherapy studies. Using the double gene transfection approach, both hepa 1-6 and SMCC-1 cell lines were successfully converted from poorly immunogenic to immunogenic.…”

An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules

“…42 A further application of the bs vaccine, which is supported by the data of this study, could consist of an ex vivo activation and expansion of patient-derived T cells for later reinfusion for adoptive cellular immunotherapy. 43 Recently, it was demonstrated in an animal tumor model 44 that bsCD28 vaccine was better than a B7-transfected vaccine. It was able to induce tumor-specific T-cell responses in vitro and had immunotherapeutic effects in vivo, leading to a regression of established tumors.…”

Treatment of hepatocellular carcinoma with adenoviral vector-mediated Flt3 ligand gene therapy

“…19 On day 10, mice with nodules ranging from 5 to 7 mm in diameter were injected with 10 9 efu of Ad-mFL, Ad-GFP (a control adenovirus) or saline buffer (PBS). As shown in Figure 2a, a potent antitumor therapeutic effect of Ad-mFL against hepa 1-6 cells-derived tumors was observed.…”