T cell receptor signaling-responsive protein nanogels for the T cell-mediated treatment of solid liver tumors
Hematology, Oncology
Final Report Abstract
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. In a first approach, T cell receptor signaling-responsive nanogels based on a single-chain version of IL-12 were developed, optimized and tested as an immunotherapeutic adjuvant with adoptive CD8+ T cell transfer in mouse tumor models. Unfortunately, nanogels “backpacked” onto T cells membranes were rapidly cleared by internalization and IL-12 released from nanogels exhibited substantial loss in bioactivity. Thus, these novel IL-12 nanogels did not induce anti-tumor responses in a mouse model of melanoma and an alternative delivery technology for IL-12 was needed. Amphiphilic conjugates of the pegylated phospholipid 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG2k) and IL-12 were synthesized (amph-scIL-12) and tested for their potential to be applied in T cell-based delivery approaches. Main setbacks thereby were: (a) a rapid internalization following incorporation of the conjugate into T cell membranes and (b) a 30- fold loss in bioactivity due to non-site-specific conjugation of DSPE-PEG2k-maleimide to native cysteines within the IL-12 amino acid sequence using the maleimide/thiol chemistry. Nevertheless, amph-scIL-12 proved to be efficient in liver trafficking following T cell-free intravenous injections and was able to induce substantial anti-tumor responses in a transgenic model of spontaneous hepatocellular carcinoma leading to tumor remission and prolonged survival. In future studies the bioactivity of the amph-scIL-12 conjugate will be improved by applying a sortase-mediated conjugation technique ensuring a site-specific coupling of DSPE-PEG2k to the C-terminus of scIL-12. With this approach the bioactivity of IL-12 will presumably be preserved and anti-tumor responses will be enhanced.
Publications
- (2019) Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365(6449):162-168
Ma L, Dichwalkar T, Chang JYH, Cosette B, Garafola D, Zhang AQ, Fichter M, Wang C, Liang S, Silva M, Kumari S, Mehta NK, Abraham W, Thai N, Li N, Wittrup KD, Irvine DJ
(See online at https://doi.org/10.1126/science.aav8692)
