Helena Florindo
Unveiling Solid TUmor Microenvironment for revolutionary nano-immunotherapies
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, but also to potentiate their delivery to the TME. Cy5.5-labeled NP were extensively internalized by DC and triggered their activation in vivo. Higher levels of DC-related 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.
References
- K. Hiam-Galvez K, et al. Nat Rev Cancer 2021, 21, 345.
- M. A. Mintz, J.G. Cyster. Immunol Rev 2020, 296, 48.
- J. Conniot et al. Nat Nanotech 2019, 2, 105.
Biography/Link
Helena Florindo graduated in Pharmaceutical Sciences in 2003 (University of Lisbon) and obtained her Ph.D. degree in Pharmaceutical Technology in 2008 (University of Lisbon), in collaboration with the University of London.
Currently, she is a Full Professor in the Department of Pharmacy, Pharmacology, and Health Technologies at the Faculty of Pharmacy, University of Lisbon. Since 2015, she has been the head of the BioNanoSciences – Drug Delivery & Immunoengineering Research Group, at the Research Institute for Medicines (iMed.ULisboa), University of Lisbon.
Helena is also a member of the Portuguese Medicines Agency Evaluation Board (INFARMED) and an expert to the European Medicines Agency (EMA), thus supporting the evaluation of marketing authorization procedures for new drugs and biologics. This knowledge in regulatory sciences also guides the research within her research group, which has been motivated by the immune-oncology field toward the rational development of functionalized nanobiomaterials as novel immunotherapies for cancer treatment. It includes the characterization of the anti-tumor effects induced by the combination of nano-vaccines with nano-therapeutics designed to modulate the functions of key cells within the tumor microenvironment, such as T cells, myeloid-derived cells, and tumor cells.
Her major topics of research are:
- Regulation of immunity by targeting dendritic cells (DC) using nanotechnology-based tools to combine the antigen-carry capacity of nanoparticles (NP) and the specific targeting and maturation of DC receptors in vivo. It aims to i) enhance antigen delivery to DC; ii) modulate antigen intracellular processing and presentation pathways; and iii) block signaling pathways related to tumor evasion mechanisms.
- Size-based targeting of lymph node-resident immune cells by NP to overcome major barriers for vaccine components and immunotherapies.
- Characterization of bio-responsive materials’ impact on germinal center response to generally improve vaccine efficacy.
- Dissecting tumor stromal and immune cell interplay to guide the design of multi-targeting nano-conjugates as innovative immunotherapeutic treatments against metastatic cancer diseases. Our recent work is focused on the characterization of the interplay of immune cells-lymphatic endothelial cells-tumor cells, especially in the brain, which knowledge we are using to tailor nano-therapeutic development.