Abstract 3575: Cell therapy with surface-tethered IL-12 improves anti-tumor efficacy and activates the endogenous immune system
Authors: Jon Nardozzi, Elena Geretti, De-Kuan Chang, Douglas W. McMillin, Jesse Lyons, Ulrik Nielsen, Thomas Andresen, Douglas Jones
Journal: Cancer Research (2018)

Abstract Adoptive cellular therapy (ACT) has shown impressive clinical responses in some hematologic malignancies. Progress for ACT in solid tumors, however, has been comparatively limited. A key challenge has been overcoming the immunosuppressive microenvironment of solid tumors, which limits T cell activation and persistence. To overcome this barrier, we have further developed our Deep PrimingTM platform to support delivery of therapeutic payloads that activate both the adaptive and innate immune system in the tumor microenvironment. Our Deep PrimingTM technology was designed to function predominantly in an autocrine fashion. To enable transpresentation and paracrine activity we ‘tethered' cytokines to the T cell surface by constructing a fusion between an immunostimulatory cytokine and an antibody targeting abundant receptors on the T cell surface. This approach is versatile and enables tunable loading and persistence of multiple cytokines on the T cell surface. It also complements transgenic TCR and CAR-T cell therapies without the additional complexities or potential risks associated with further genetic engineering. Interleukin-12 (IL-12) is a potent cytokine with the potential to reshape the anti-inflammatory environment in solid tumors. However, its clinical utility has been limited by severe toxicities both from soluble administration or from adoptively transferred T cells engineered to secrete IL-12. By linking IL-12 to antibodies targeting T cell surface receptors such as CD45 we have improved control of dose and distribution. In in vitro model systems, surface-tethered IL-12 activated signaling on both the loaded T cells and on co-incubated, non-tethered cells (p&amp;lt;0.002), confirming their ability to signal in both cis and trans. Utilizing the Pmel model, which contains CD8 T cells specific to the gp100 antigen expressed in B16-F10 melanoma cells, we evaluated the ability of the IL-12 tethered fusion to augment ACT in vivo. Pmel T cells that were loaded ex vivo with surface-tethered IL-12 significantly improved anti-tumor activity against established B16 tumors compared with Pmel cells alone. The tethered IL-12 additionally activated the endogenous immune system, inducing a rapid transient lymphopenia of both transferred and endogenous CD8 T cells as well as endogenous NK cells (p&amp;lt;0.0001). This was followed by robust proliferation and activation of NK cells (p&amp;lt;0.0001) and proliferation and differentiation of CD8 T cells (p&amp;lt; 0.001). These effects were transient and returned to baseline within two weeks and resulted in minimal overt toxicity (3.3% avg body wt loss). Further analysis of preclinical safety will be discussed. This approach leverages the ability of T cells to traffic and accumulate within the tumor and holds potential to overcome the immunosuppressive environment associated with solid tumors. Citation Format: Jon Nardozzi, Elena Geretti, De-Kuan Chang, Douglas W. McMillin, Jesse Lyons, Ulrik Nielsen, Thomas Andresen, Douglas Jones. Cell therapy with surface-tethered IL-12 improves anti-tumor efficacy and activates the endogenous immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3575.