IL-12 Surface-Tethering: Boosting Tumor-Specific T-Cell Responses and Local Inflammation Without Systemic Toxicity

Interleukin-12 (IL-12) is recognized for its ability to enhance anti-tumor immunity by stimulating T cell differentiation and cytotoxicity among other immune functions. However, systemic administration of IL-12 has faced limitations due to associated toxicities. A novel approach involves DeepTM IL-12, a fusion protein that attaches IL-12 to T cells via a Fab antibody against CD45, aiming to concentrate its effects within the tumor microenvironment and reduce toxicity.

In this study, the safety and efficacy of Deep IL-12 were assessed using a cancer model involving CD8 PMEL T cells, which are primed with a TCR that targets the gp100 antigen found in B16-F10 melanoma cells. The Deep IL-12 Primed T cells were transferred into mice with established tumors and compared against treatments using standard PMEL T cells or those co-administered with systemic IL-12.

The results demonstrated that the Deep IL-12 Primed T cells significantly improved tumor inhibition and survival rates without causing overt toxicities, unlike the systemic IL-12 co-administration. These primed T cells induced sustained IFNγ within the tumor environment, while avoiding systemic IFNγ induction which returned to normal levels quickly post-treatment. The Deep IL-12 Priming strategy also enhanced the accumulation and activity of the transferred T cells specifically in the tumor area, not affecting off-target tissues such as the spleen.

The study concludes that by tethering IL-12 to tumor-specific T cells, the Deep IL-12 Priming method enhances the therapeutic effectiveness of T cells in the tumor microenvironment while minimizing systemic exposure and toxicity, offering a promising therapeutic strategy for solid tumors. Further toxicological evaluations of these Deep IL-12 Primed tumor-reactive T cells will be discussed, highlighting their potential benefit-risk profile.