(531f) A Stimuli-Responsive Immunomodulation Platform for Cancer Therapy

Breast cancer is a major leading cause of death worldwide and current advances in cancer treatment are focusing on targeted therapy and immunotherapy. Immunotherapy is an efficient cancer treatment yet faces many challenges including difficulties in targeting solid tumor, possible severe side effects, and a relatively-low response rate around 5-20% in metastatic breast cancer patients due to immunosuppressive tumor environment.1 Recent studies have demonstrated that stimuli-responsive prodrugs offer spatial and temporal control, while limitations in delivery efficiency, cell permeability, and immunogenicity still exist in clinical applications. To overcome these challenges, our group has previously developed a drug delivery platform that spatiotemporally delivers STING (stimulator of interferon genes) agonist through selective binding to immune checkpoint inhibitors and albumin hitchhiking. Moving forward, we are engineering a photo-induced platform to enhance tumor-specific delivery of cancer therapeutics. We will generate a recombinant protein library by conjugating a tumor-targeting nanobody to an engineered therapeutic peptide with a synthetic photo-protecting group. After systemic administration, the photo-protecting group undergoes traceless release by external light stimulus at the tumor microenvironment to generate a functionally active peptide moiety, serving as a prodrug strategy for logic-gated immune activation. Cellular uptake and lysosomal release of the therapeutic peptide enables tumor-specific activation of immune cells, including NK and CD8+ T cells. Our in vitro studies validate the protein binding affinity, activation profile for the carrier system, and therapeutic efficacy of our modular platform. Future in vivo work within our group will evaluate the pharmacokinetic profile, biodistribution, and anti-tumor efficacy of the protein carrier system. Using this strategy, we anticipate that our drug delivery system may offer increased bioavailability and activation at the target sites, and we will be able to achieve site-specific delivery of immunotherapeutic.

Reference:

1. Debien, V.; De Caluwé, A.; Wang, X.; Piccart-Gebhart, M.; Tuohy, V. K.; Romano, E.; Buisseret, L. Immunotherapy in Breast Cancer: An Overview of Current Strategies and Perspectives. Npj Breast Cancer 2023, 9 (1), 7. https://doi.org/10.1038/s41523-023-00508-3.