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Intratumoral expression using a NFkB-based promoter enhances IL12 antitumor efficacy

AuthorsGaraulet, Guillermo; Pérez-Chacón, Gema ; Alarcon, Helena; Alfranca, Arántzazu; Mulero, Francisca; Martínez Torrecuadrada, Jorge Luis; Zapata, Juan M. ; Rodríguez, Antonio
Issue Date2019
CitationCancer Gene Therapy 26(7-8): 216-233 (2019)
AbstractInterleukin 12 is a promising anti-cancer agent; however, IL12 systemic administration is hampered by side-effects. Although intratumoral administration of IL12 is giving promising results in clinical trials, only a small percentage of patients show a complete therapeutic response. This outcome could be improved by controlling the IL12 expression window. In this work we have tested the efficacy of a self-processing P2A and codon optimized murine IL12 (mIL12Pop) using inflammation-regulated lentivectors in a syngeneic tumor model. Our results show that implantation of cells expressing mIL12Pop employing either the strong constitutive SFFV promoter or a NFkB-based promoter reduced tumor growth, caused CD8+ T cell activation and increased IFNγ production. Importantly, the use of NFkBp-mIL12Pop increased the number of CD8+ TILs and improved the remission rate without increasing IL12-serum concentration. Further experiments suggest that there is a threshold intratumoral IL12 concentration that must be reached to trigger an efficient antitumor response and a limit that once surpassed causes detrimental systemic side effects. Altogether, these results demonstrate that using NFKBp-mIL12Pop significantly increases the overall survival of the mice. In summary, this new inflammation-regulated expression system might be useful for the development of new IL12 delivery systems with improved anti-tumor activity and limited toxicity.
Publisher version (URL)https://doi.org/10.1038/s41417-018-0076-4
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