4.2.3. Artificial Antigen Presentation Cells (aAPC)

Artificial antigen-presenting cells (aAPC) deliver stimulation signals to cytotoxic T cells and are a powerful tool for active and adoptive immunotherapy [228].

In fact, the induction of specific cytotoxic T cell (CTL) responses is a potent therapy against pathogens and tumours. Specific CTLs produce robust responses and generate long-term memory [229]. As an active immunotherapy, CTLs can be activated in vivo.

Two signals are required from APCs for T cell activation, the first being a related antigenic peptide presented on MHC molecules that binds to the TCR, and the second a series of co-stimulatory receptors that modulate T cell response [230]. In immunotherapy, modified NPs that function as artificial antigen-presenting cells (aAPCs) are being used to rapidly expand tumour-specific T cells from naïve precursors and responses to predicted neo-epitopes [231].

Naïve tumour-specific precursors are rare and APC-based methods for the expansion of naïve tumour-specific cells will require continued stimulation during multiple tabletop sessions, followed by T-cell selection and subcloning to generate the number of tumour-specific cells required for adoptive immunotherapy. Therefore, the development of the ideal T-cell expansion platform is required, which generates robust expansion, minimizing culture time and costs [231].

As an example, the study described by Karlo Perica et al., iron-dextran NPs were used and a chimeric immunoglobulin-MHC dimer (MHC-Ig) loaded with a specific peptide is used to generate signal 1 and B7.1 (natural T-cell receptor ligand CD28) or an activating antibody against CD28 is used for signal 2. These molecules are chemically bonded to the surface of the microspheres to generate these aAPCs. It was found that the aAPCs induced antigen-specific T cell expansion in vitro and that both signals were essential for optimal expansion, and also induced anti-tumour activity in vivo. In addition, the amount and density of antigen presented by APCs are known to influence T cell behaviour, proliferation and cell death, and therefore are important parameters to consider in aAPC stimulation [228].

The potential sites where aAPCs may be most effective are the lymph nodes, where the naive and memory T cells are found, and the site of the tumour [228]. In addition, aAPCs may overcome one of the major obstacles in cancer immunotherapy: the tumour's immunosuppressive microenvironment. This is because they deliver the immunostimulatory signal in situ [232]. aAPCs are known to activate T cells by specific receptor-ligand bonds at the cell-sphere interface, but such interactions are not defined at the nanoscale level [233].

Although nanoscale aAPCs have been shown to induce anti-tumour naïve T-cell populations in vivo, the ability of these nanostructures to mediate the rejection of established tumours in highly immunosuppressive microenvironments has not been determined. It is not yet well-known whether a local stimulating signal could overcome several stages of tumour immunosuppression, or even whether aAPC-based stimulation could be enhanced by other immunomodulatory therapies such as checkpoint blocking strategies [228].

Although autologous APCs (DC, monocytes and activated B cells) have originally been used to generate tumour-specific T cells in vitro, this requires regular access to patients' blood and, in addition, the quantity and quality of each patient's autologous APCs is variable. APCAs overcome these problems, are easy to produce and allow reliable expansion of antigen-specific T-cell populations, as we have already seen, making them a promising technology for cancer immunotherapy [234,235].
