CMRF-56 immunoselected blood dendritic cell preparations activated with GM-CSF induce potent antimyeloma cytotoxic T-cell responses.
The efficient antigen-presenting function of dendritic cells (DC) makes them an attractive cellular adjuvant for clinical immunotherapeutic protocols aimed at eradicating minimal residual disease after conventional treatment of multiple myeloma (MM) and other malignancies. We used single-step positive immunoselection with biotinylated CMRF-56 monoclonal antibody to generate a CD11c blood DC (BDC) enriched antigen-presenting cell population, which, after exposure to activation stimuli for as little as 2 hours, displayed a mature costimulatory BDC phenotype and secreted inflammatory cytokines. Of the activation stimuli tested, granulocyte macrophage colony-stimulating factor (GM-CSF) provided optimal activation of the CMRF-56 immunoselected preparations and primed efficient cytotoxic T cell (CTL) responses using MART-1 peptide as a model tumor-associated antigen. In addition, GM-CSF activated CMRF-56 immunoselected cells cross-presented MM cell lysate and improved the MM-specific polyclonal CTL response (no activation 18.8%+/-4.3% vs. GM-CSF activation 40.9%+/-7.3%, P=0.051). CMRF-56 immunoselected BDC migrated in vitro both spontaneously and specifically toward the secondary lymphoid chemokine CCL21. Their migration was also significantly improved by GM-CSF and prostaglandin E2 activation and a greater percentage of activated BDC migrated specifically compared with monocyte-derived DC. These results indicate that the CMRF-56 immunoselected BDC preparations can cross-present antigen for effective anti-MM CTL responses and that limited exposure to maturation stimuli can produce phenotypically and functionally mature migrating DC. CMRF-56 immunoselected cells are suitable for use as part of an immunotherapeutic anti-MM vaccine.
Freeman
Jennifer L
JL
Mater Medical Research Institute, South Brisbane, Queensland, Australia.
Vari
Frank
F
Hart
Derek N J
DN
D000911:Antibodies, Monoclonal; D017951:Antigen Presentation; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000943:Antigens, Differentiation / Q000276:immunology* / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D058965:MART-1 Antigen; D009101:Multiple Myeloma / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; C119956:CMRF-56 antigen; D016207:Cytokines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor