Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment

Mol Ther. 2011 Apr;19(4):751-9. doi: 10.1038/mt.2010.313. Epub 2011 Feb 1.


Interleukin-12 (IL-12) is an important immunostimulatory cytokine, yet its clinical application has been limited by the systemic toxicity associated with its administration. In this work, we developed a strategy to selectively deliver IL-12 to the tumor environment using genetically engineered lymphocytes. However, peripheral blood lymphocytes (PBLs) transduced with a γ-retroviral vector, which constitutively expressed IL-12, failed to expand in culture due to apoptosis. To circumvent this problem, a vector was designed where IL-12 expression was directed by a composite promoter-containing binding motifs for nuclear factor of activated T-cells (NFAT.hIL12.PA2). The NFAT-responsive promoter was activated to drive IL-12 expression upon the recognition of tumor-specific antigen mediated by a T cell receptor (TCR) that was engineered into the same lymphocytes. We tested the efficacy of the inducible IL-12 vector in vivo in a murine melanoma model. Adoptive transfer of pmel-1 T cells genetically engineered with NFAT-murineIL12 (NFAT.mIL12.PA2) significantly enhanced regression of large established B16 melanoma. Notably, this targeted and controlled IL-12 treatment was without toxicity. Taken together, our results suggest that using the NFAT.hIL12.PA2 vector might be a promising approach to enhance adoptive cancer immunotherapy.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Flow Cytometry
  • Genetic Vectors / genetics
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Interleukin-12 / genetics
  • Interleukin-12 / metabolism*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / therapy*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • Retroviridae / genetics


  • Receptors, Antigen, T-Cell
  • Interleukin-12