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

Published

Journal Article

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.

Full Text

Cited Authors

  • Zhang, L; Kerkar, SP; Yu, Z; Zheng, Z; Yang, S; Restifo, NP; Rosenberg, SA; Morgan, RA

Published Date

  • April 2011

Published In

Volume / Issue

  • 19 / 4

Start / End Page

  • 751 - 759

PubMed ID

  • 21285960

Pubmed Central ID

  • 21285960

Electronic International Standard Serial Number (EISSN)

  • 1525-0024

International Standard Serial Number (ISSN)

  • 1525-0016

Digital Object Identifier (DOI)

  • 10.1038/mt.2010.313

Language

  • eng