Advancing Cancer Immunotherapy with Nanomedicine

In her thesis, G. Choukrani focused on developing (nano)immunotherapy into a versatile and applicable concept by addressing various outstanding challenges. Specifically, she started with investigating potential suitable immunotherapeutic targets for use in (nano)immunotherapy (Galectin-9 and VISTA), since novel therapeutics with unique modes-of-action are urgently needed. Galectin-9, a carbohydrate protein with several biological functions, was found to be effective in fighting cancer by increasing neutrophil-mediated anticancer activity and interfering with autophagy in Acute Myeloid Leukemia (AML) and Cytarabine-resistant AML. VISTA, on the other hand, was found to enhance macrophage-mediated phagocytosis of cancer cells but also decreased anti-inflammatory signals and antigen-specific TCR-mediated activation of T cells. This means that VISTA (V-Domain Ig Suppressor of T Cell Activation) is a negative regulator in macrophage-mediated anticancer activity and may be targeted with blocking antibodies. However, using such immunotherapeutic drugs may cause off-target toxicity upon systemic delivery. To circumvent this issue, they may be incorporated into a nanoimmunotherapy approach using drug delivery systems (DDS) to enhance tumor selectivity. Hereto, a suitable nanocarrier, vaterite nanoparticles (VNP), was identified for loading and tumor microenvironment-localized release of immunologically active proteins. VNP was proven to load a variety of immunotherapeutic proteins and release them specifically at the low pH of the TME, potentially reducing off-target effects. Furthermore, a prototype immunological protein was integrated into the developed nanoparticle and this combination was further tailored for target antigen-restricted delivery and tumor-specific release. Of note, the developed nanoparticle-based DDS offers a high degree of versatility, making it suitable for various applications, including pre-targeting. Overall, the research described in this thesis highlights the potential of Galectin-9 and VISTA as targets for cancer immunotherapy. Moreover, it provides a framework for using VNP-based DDS to improve cancer treatment to help address some of the critical challenges associated with cancer immunotherapy.