Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment.
|
| Abstract |
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.
|
|---|---|
| Authors | Ling Zhang, Sid P Kerkar, Zhiya Yu, Zhili Zheng, Shicheng Yang, Nicholas P Restifo, Steven A Rosenberg, Richard A Morgan |
| Journal | Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 4 Pg. 751-9 (Apr 2011) ISSN: 1525-0024 [Electronic] United States |
| PMID | 21285960 (Publication Type: Journal Article, Research Support, N.I.H., Intramural) |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!