Harnessing T Cells with Surface-Tethered IL-12: Boosting Anti-Tumor Response and Immune System Activation

Adoptive cellular therapy has demonstrated significant clinical benefits in certain blood cancers, but its success in treating solid tumors has been less pronounced due to the challenging immunosuppressive tumor microenvironment. To address this, a novel Deep Priming platform has been developed to enhance both adaptive and innate immune responses within the tumor microenvironment. This technology utilizes an autocrine mechanism and introduces a method of 'tethering' cytokines to T cells by creating a fusion with an immunostimulatory cytokine and an antibody that targets receptors on the T cell surface. This strategy is adaptable, allowing for adjustable cytokine loading and retention on T cells, and complements existing TCR and CAR-T cell therapies without additional genetic manipulation.

Interleukin-12 (IL-12) is a powerful cytokine capable of altering the anti-inflammatory tumor environment, but its clinical use has been hindered by severe side effects. By attaching IL-12 to antibodies that target T cell surface receptors like CD45, the dosage and distribution are better managed. In vitro testing showed that T cells with surface-tethered IL-12 activated signaling in both the attached and nearby cells, indicating cis and trans signaling capabilities.

Using the Pmel model, which includes CD8 T cells reactive to the gp100 antigen found in B16-F10 melanoma cells, the efficacy of surface-tethered IL-12 in boosting ACT was assessed in vivo. Pmel T cells equipped with surface-tethered IL-12 displayed enhanced anti-tumor effects against established B16 tumors compared to untreated cells. The tethered IL-12 also stimulated the native immune system, leading to a brief lymphopenia in both transferred and native CD8 T cells and native NK cells, followed by a strong proliferation and activation of NK cells and the proliferation and differentiation of CD8 T cells. These effects were temporary, resolving within two weeks, and resulted in minimal toxicity.

The study will further discuss the preclinical safety analysis of this method, which takes advantage of T cells' ability to infiltrate and concentrate within tumors, offering a potential solution to the immunosuppressive challenges posed by solid tumors.

Citation: Jon Nardozzi, Elena Geretti, De-Kuan Chang, Douglas W. McMillin, Jesse Lyons, Ulrik Nielsen, Thomas Andresen, Douglas Jones. Enhancement of anti-tumor activity and endogenous immune system activation through cell therapy with surface-tethered IL-12 [abstract]. Proceedings of the American Association for Cancer Research Annual Meeting 2018; Chicago, IL; April 14-18, 2018. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3575.