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

Interleukin 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.
AR is supported by the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2012-32166) and the Comunidad Autonoma de Madrid, Spain (S2010/BMD-2312). FM is supported by the Comunidad Autonoma de Madrid, Spain (S2017/BMD-3867) and co-financed by European Structural and Investment Funds. AA and JMZ are supported by the Instituto de Salud Carlos III, Spain (PI15/01491 and PI16/00895, respectively). H.A. holds a research fellowship from Spanish Ministry of Education, Culture and Sports (MECD).