Open AccessLocalized interleukin‐12 delivery for immunotherapy of solid tumours
Author(s) -
Wei Louis Z.,
Xu Yixin,
E. Nelles Megan,
Furlonger Caren,
Wang James C.M.,
Di Grappa Marco A.,
Khokha Rama,
Medin Jeffrey A.,
Paige Christopher J.
Publication year - 2013
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12121
Subject(s) - immunotherapy , antibody , cytokine , cancer immunotherapy , cell culture , cancer research , cell , interleukin 12 , immunology , chemistry , biology , in vitro , immune system , cytotoxic t cell , biochemistry , genetics
Interleukin ( IL )‐12 is the key cytokine in the initiation of a Th1 response and has shown promise as an anti‐cancer agent; however, clinical trials involving IL ‐12 have been unsuccessful due to toxic side‐effects. To address this issue, lentiviral vectors were used to transduce tumour cell lines that were injected as an autologous tumour cell vaccine. The focus of the current study was to test the efficacy of this approach in a solid tumour model. SCC VII cells that were transduced to produce IL ‐12 at different concentrations were then isolated. Subcutaneous injection of parental SCC VII cells results in tumour development, while a mixture of IL ‐12‐producing and non‐producing cells results in tumour clearance. Interestingly, when comparing mice injected a mixture of SCC VII and either high IL ‐12‐producing tumour cells or low IL ‐12‐producing tumour cells, we observed that mixtures containing small amounts of high producing cells lead to tumour clearance, whereas mixtures containing large amounts of low producing cells fail to elicit protection, despite the production of equal amounts of total IL ‐12 in both mixtures. Furthermore, immunizing mice with IL ‐12‐producing cells leads to the establishment of both local and systemic immunity against challenge with SCC VII. Using depletion antibodies, it was shown that both CD 4 + and CD 8 + cells are crucial for therapy. Lastly, we have established cell clones of other solid tumour cell lines ( RM ‐1, LLC 1 and moto1.1) that produce IL ‐12. Our results show that the delivery of IL ‐12 by cancer cells is an effective route for immune activation.