Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 135, Issue 2, Pages 322-329Publisher
BLACKWELL PUBLISHING LTD
DOI: 10.1111/j.1365-2249.2004.02360.x
Keywords
IL-12; T lymphocyte; cytokine; tumour antigen; peptide
Categories
Funding
- NCI NIH HHS [R01CA85374, K24CA85218, R01 CA085374, K24 CA085218] Funding Source: Medline
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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.
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