title: In vitro co-stimulation with anti-CD28 synergizes with IL-12 in the generation of T cell immune responses to leukaemic cells; a strategy for ex-vivo generation of CTL for immunotherapy.
abstract: The existence of an immune based graft-versus-leukaemia (GvL) effect highlighted the prospect of managing relapsed leukaemias with T cell-based adoptive immunotherapy. Thus, various strategies have been explored for the in vitro expansion of acute myeloid leukaemia (AML)-specific T cells. In a popular approach, AML blasts have been genetically modified to express co-stimulatory molecules essential for effective T cell priming. One such tactic has been the modification of AML cells to express the B7/CD80 co-stimulatory molecule that binds to CD28 on T cells initiating events that culminate in enhanced cytokine production, proliferation and development of effector functions by T cells. The success of these strategies has been limited by difficulties in attaining sufficient transduction efficiencies and associated high levels of CD80 expression. We demonstrate that these problems can be circumvented by using anti-CD28 monoclonal antibody. Furthermore, we show that the synergistic relationship between CD80/CD28 pathway and interleukin 12 cytokine (IL-12), documented in the generation of cytotoxic T lymphocytes (CTL) for solid tumours, also applies to AML. CD28/IL-12 synergy facilitated the proliferation of allogeneic T cells in response to stimulation with primary AML blasts. The synergy also favoured generation of a Th1-type immune response, evidenced by gamma interferon (IFN-gamma) secretion and facilitated naive and memory T cell proliferation. Unlike some methods of in vitro T cell expansion, use of CD28/IL-12 synergy left T cells in the physiologically appropriate CD45RA-/CCR7- subsets known to be associated with immediate cytotoxic functions.
authors.affiliation: Department of Haematology, Royal Free and University College Medical School, London, UK.
authors.forename: J K
authors.initials: JK
authors.lastname: Orleans-Lindsay
authors.forename: A
authors.initials: A
authors.lastname: Deru
authors.forename: J I O
authors.initials: JI
authors.lastname: Craig
authors.forename: H G
authors.initials: HG
authors.lastname: Prentice
authors.forename: M W
authors.initials: MW
authors.lastname: Lowdell
mesh_terms: D000208:Acute Disease; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018122:B7-1 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D020544:Graft vs Leukemia Effect; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology*; D007951:Leukemia, Myeloid / Q000276:immunology / Q000628:therapy*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008562:Membrane Glycoproteins / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; C515370:CCR7 protein, human; D018106:CD28 Antigens; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D054353:Perforin; D018664:Interleukin-12; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens