Abstract 933: Surface-tethered IL-12 improves tumor-specific T-cell therapy and enhances inflammatory activity in tumors without inducing systemic toxicities
Authors: Chang De-Kuan , Ahmad Gulzar , Nardozzi Jonathan , Sackton Katharine , Lyons Jesse , Sauer Karsten , Andresen Thomas , Jones Douglas 
Published: August 2019

Introduction Interleukin-12 (IL-12) is a potent cytokine that augments anti-tumor immune responses by promoting CD4 T cell Th1 differentiation, increasing CD8 T cell and NK cell cytotoxicity, inducing MHC expression on antigen presenting cells, and reprogramming myeloid-derived suppressor cells. However, the clinical utility of IL-12 administered systemically or produced by genetically engineered tumor-specific T cells has been limited by toxicities. DeepTM IL-12 is a fusion protein between IL-12 and a Fab antibody against CD45, an abundant surface receptor on T cells. This tethers IL-12 onto tumor-specific T cells prior to adoptive cell transfer (ACT) with the aim of reducing systemic exposure and focusing IL-12 function on the tumor microenvironment. Here, we describe the superior safety and efficacy profiles of Deep IL-12 tethered T cells in an immune competent adoptive cell therapy model for solid tumors.

Methods The safety and efficacy of Deep IL-12 Primed T cells were evaluated in the PMEL/B16-F10 cancer model. CD8 PMEL T cells contain a TCR that recognizes the gp100 antigen expressed in B16-F10 melanoma cells. Deep IL-12 was loaded onto PMEL CD8 T cells to generate Deep IL-12 Primed PMEL T cells which were then adoptively transferred into mice bearing B16-F10 tumors. We compared tumor size, body weight change, cytokine release, circulating toxicity biomarkers, immune cell activity and histopathology in mice treated with Deep IL-12 Primed T cells and PMEL T cells alone or co-administered with recombinant IL-12.

Results Deep IL-12 Primed PMEL T cells significantly improved tumor growth inhibition and overall survival in mice bearing established B16-F10 tumors as compared with PMEL T cell therapy alone or combined with systemic co-administration of IL-12. Deep IL-12 Primed PMEL

T cells were well-tolerated, as administration of at least 40 million Deep IL-12 Primed PMEL T cells did not cause overt toxicities in non-tumor bearing mice. Deep IL-12 Primed PMEL T cells, but not PMEL T cells combined with systemic IL-12, resulted in elevated and sustained induction of IFNγ in the tumor microenvironment. In contrast, IFNγ induction in serum was transient and returned to baseline levels within four days of ACT. Interestingly, Deep IL-12 Priming increased both accumulation and activity of the adoptively transferred PMEL T cells in the tumor microenvironment but not in off-target healthy tissues such as the spleen. Further toxicological analysis of Deep IL-12 Primed tumor-reactive T cells will be discussed.

Conclusions Deep IL-12 Priming enables tethering of IL-12 to the surface of tumor-specific T cells prior to ACT. This improves anti-tumor efficacy by promoting T cell function selectively in the tumor microenvironment and avoids toxicity by limiting systemic IL-12 exposure, resulting in a highly favorable benefit-risk profile for Deep IL-12 Primed T cells.

Citation Format: De-Kuan Chang, Gulzar Ahmad, Jonathan Nardozzi, Katharine Sackton, Jesse Lyons, Karsten Sauer, Thomas Andresen, Douglas Jones. Surface-tethered IL-12 improves tumor-specific T-cell therapy and enhances inflammatory activity in tumors without inducing systemic toxicities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 933.