IL-12 enhances the generation of tumour antigen-specific Th1 CD4 T cells during ex vivo expansion

Keith L Knutson, M. L. Disis

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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-γ and TNF-α).The increased proliferative response of the cultures was due in part to an increase in the number of HER-2/neu-specificT 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.

Original languageEnglish (US)
Pages (from-to)322-329
Number of pages8
JournalClinical and Experimental Immunology
Volume135
Issue number2
DOIs
StatePublished - Feb 2004
Externally publishedYes

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Neoplasm Antigens
Interleukin-12
T-Lymphocytes
Antigens
Interleukin-2
Cytokines
Cell- and Tissue-Based Therapy
Adoptive Immunotherapy
Neoplasms
CD4 Antigens
Subunit Vaccines
Preexisting Condition Coverage
Helper-Inducer T-Lymphocytes
Epitopes
Immunity
Vaccination
Maintenance
Cell Line
Peptides

Keywords

  • Cytokine
  • IL-12
  • Peptide
  • T lymphocyte
  • Tumour antigen

ASJC Scopus subject areas

  • Immunology

Cite this

IL-12 enhances the generation of tumour antigen-specific Th1 CD4 T cells during ex vivo expansion. / Knutson, Keith L; Disis, M. L.

In: Clinical and Experimental Immunology, Vol. 135, No. 2, 02.2004, p. 322-329.

Research output: Contribution to journalArticle

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abstract = "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-γ and TNF-α).The increased proliferative response of the cultures was due in part to an increase in the number of HER-2/neu-specificT 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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