T cell receptor signaling-responsive protein nanogels for the T cell-mediated treatment of solid liver tumors

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Hepatocellular carcinoma (HCC) is the fifth most common form of cancer and the third leading cause of cancer-related deaths worldwide. Occurrence is associated with poor prognosis and the treatment options are limited. Immunotherapy has shown promising results in other cancer types, such as melanoma or B cell malignancies. However, the limited success of immunotherapeutic treatment approaches for HCC is at least partly due to the immunosuppressive microenvironment inherent in the liver and even more pronounced in solid liver tumors. As such, the development of novel strategies to overcome the state of tolerance in the liver and to stimulate tumor-specific T cells is of great importance. Therefore, the focus of the proposed study will be the development and characterization of novel T cell receptor (TCR) signaling-responsive nanogel formulations for immunotherapeutic treatment using adoptive T cell transfer in a mouse model of hepatocellular carcinoma. Nanogels will be synthesized based on different immunostimulatory cytokines or antibodies, such as anti-PD-1, anti-CTLA-4, anti-IL-10, anti-TGFβ, OX40 ligand or IL-12, by crosslinking of protein molecules and introducing redox-sensitive disulphide bonds. The capability of the generated nanogel formulations to target and bind to the plasma membrane of T cells and their potential to release protein cargo upon TCR ligation will be investigated. In a next step, nanogels will be evaluated in terms of activation of antigen-specific CD8+ T cells in vitro and the subsequent killing of antigen-expressing hepatocytes. In final investigations, the nanogel-loaded CD8+ T cells will be adoptively transferred in recipient mice with antigen-expressing hepatocytes or in mice bearing a tumor model of hepatocellular carcinoma. Treatment success will be analyzed measuring liver homing and intrahepatic expansion of adoptively transferred T cells, the antigen-specific lysis of hepatocytes, tumor growth, and the survival of tumor-bearing mice.