IL-12 enhances the generation of tumour antigen-specific Th1 CD4 T cells during ex vivo expansion.
CD4+ T cells are essential for the immune response against cancer. Vaccination against cancer will likely only be effective at preventing growth of micrometastatic disease while adoptive T cell therapy will be better suited for eradication of bulky pre-existing disease (Knutson et al. Expert Opin Biol Ther 2002; 2:55-66). Problems with the use of adoptive T cell therapy include lack of CD4+ T cell help, low frequency of antigen-specific T cells, and lack of effective ex vivo expansion techniques. In this study, we focused on improving ex vivo expansion of CD4+ T helper cells. The effects of IL-12, along with IL-2, on the ex vivo generation of HER-2/neu antigen-specific T cells were examined. Patients were immunized with a peptide-based vaccine that contained a helper epitope, p776-790, derived from the intracellular domain of HER-2/neu. While T cell immunity to p776-790, assessed by proliferation assays, could be readily measured in short-term cultures, cell line generation by multiple in vitro stimulation with peptide and IL-2 as the only added cytokine resulted in loss of antigen-specific proliferation. The inclusion of IL-12, along with IL-2, restored antigen-specific proliferation in a dose-dependent fashion. The resulting p776-790-specific T cells responded readily to antigen by proliferating and producing type I cytokines (IFN-gamma and TNF-alpha). The increased proliferative response of the cultures was due in part to an increase in the number of HER-2/neu-specific T cells. These results suggest that IL-12 is an important cytokine for ex vivo recovery and maintenance of antigen-specific CD4+ T lymphocytes that would otherwise be lost by using IL-2 alone in combination with antigen. Furthermore, these results have important implications for ex vivo expansion of CD4+ T cell for use in anti-tumour adoptive immunotherapy.
Knutson
K L
KL
Tumor Vaccine Group, Division of Oncology, University of Washington, Seattle 98195-6527, USA. kknutson@u.washington.edu
Disis
M L
ML
D000951:Antigens, Neoplasm / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D018664:Interleukin-12 / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D007371:Interferon-gamma; D018664:Interleukin-12; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D014409:Tumor Necrosis Factor-alpha