Localized interleukin-12 delivery for immunotherapy of solid tumours. J Cell Mol Med 2013 Nov;17(11):1465-74
Date
11/21/2013Pubmed ID
24251770Pubmed Central ID
PMC4117559DOI
10.1111/jcmm.12121Scopus ID
2-s2.0-84891148986 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
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. SCCVII cells that were transduced to produce IL-12 at different concentrations were then isolated. Subcutaneous injection of parental SCCVII 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 SCCVII 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 SCCVII. Using depletion antibodies, it was shown that both CD4(+) and CD8(+) cells are crucial for therapy. Lastly, we have established cell clones of other solid tumour cell lines (RM-1, LLC1 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.
Author List
Wei LZ, Xu Y, Nelles EM, Furlonger C, Wang JC, Di Grappa MA, Khokha R, Medin JA, Paige CJAuthor
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cancer Vaccines
Carcinoma, Squamous Cell
Cell Line, Tumor
Female
Head and Neck Neoplasms
Immunologic Memory
Immunotherapy
Interleukin-12
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Neoplasm Transplantation
