Lecture: "Navigating solid tumors for smart nano-vaccine therapies"

Professor Helena Florindo is a ​2024/2025 Lowy Distinguished Guest Professor of The Institute of Advanced Studies.

Abstract

Among immunotherapeutic approaches, immune checkpoint inhibitors (ICI) have revolutionized the treatment of several cancers. However, limited efficacy has been obtained for cancer vaccines, and severe immune-mediated side effects have been related to ICI under clinical development [1]. Looking into solid tumors, such as breast cancer, pancreatic cancer, and melanoma, the highly immunosuppressive tumor microenvironment (TME) and the immune evasion mechanisms have limited the infiltration by immune cells and therapeutics [2]. Here we show the synergistic therapeutic effect of nanomedicines [3] in combination with ICI in preclinical models of breast carcinoma (BC), pancreatic ductal adenocarcinoma (PDAC), and melanoma. 

Polymeric nanoparticles (NP) were designed to target dendritic cells (DC) and the TME by incorporating tumor-associated antigens, toll-like receptor ligands CpG and Poly(I:C), and regulators of potent immune suppressor molecules within the TME. NP surface was modified to promote DC activation and potentiate their delivery to the TME. Cy5.5-labeled NP were extensively internalized by DC and triggered their activation in vivo. Higher levels of DCrelated co-stimulatory molecules, such as CD80, CD86, and CD40, were observed when compared with non-carbohydrate carriers. The anti-tumor immune-mediated effect was evaluated ex vivo in patient-derived organoids and in vivo in melanoma/PDAC//BC-bearing mouse models. NP successfully induced a potent immune-mediated anti-tumor response against melanoma, PDAC, and BC. Synergistic anti-tumor effects were observed when NP was combined with ICI. The multifunctional nanomedicines re-shaped the immune profiling within the TME of melanoma, PDAC, and BC, which correlated with the overall anti-tumor effect obtained in this combinatorial scheme. In particular, 4T1 and E0771 tumor-bearing animals treated with the multifunctional nanomedicine combined with αOX40 showed a noteworthy tumor remission, with prolonged overall survival. 

In conclusion, the developed nanotechnology-based system induced a strong antigen-specific immune response and unlocked melanoma, PDAC, and BC to standard immunotherapeutic approaches, as immune checkpoint modulators.