RESUMO
Therapeutic strategies based on immunomodulation have improved cancer therapy. Most approaches target co-stimulatory pathways or the inhibition of immunosuppressive mechanisms, to enhance immune response and overcome the immune tolerance of tumors. Here, we propose a novel platform to deliver targeted immunomodulatory signaling, enhancing antitumor response. The platform is based on virus-like particles derived from lentiviral capsids. These particles may be engineered to harbor multifunctional ligands on the surface that drive tropism to the tumor site and deliver immunomodulatory signaling, boosting the antitumor response. We generated virus-like particles harboring a PSMA-ligand, TNFSF co-stimulatory ligands 4-1BBL or OX40L, and a membrane-anchored GM-CSF cytokine. The virus-like particles are driven to PSMA-expressing tumors and deliver immunomodulatory signaling from the TNFSF surface ligands and the anchored GM-CSF, inducing T cell proliferation, inhibition of regulatory T cells, and potentiating elimination of tumor cells. The PSMA-targeted particles harboring immunomodulators enhanced antitumor activity in immunocompetent challenged mice and may be explored as a potential tool for cancer immunotherapy.
RESUMO
Immunotherapy explores several strategies to enhance the host immune system's ability to detect and eliminate cancer cells. The use of antibodies that block immunological checkpoints, such as anti-programed death 1/programed death 1 ligand and cytotoxic T-lymphocyte-associated protein 4, is widely recognized to generate a long-lasting antitumor immune response in several types of cancer. Evidence indicates that the elimination of tumors by T cells is the key for tumor control. It is well known that costimulatory and coinhibitory pathways are critical regulators in the activation of T cells. Besides blocking checkpoints inhibitors, the agonistic signaling on costimulatory molecules also plays an important role in T-cell activation and antitumor response. Therefore, molecules driven to costimulatory pathways constitute promising targets in cancer therapy. The costimulation of tumor necrosis factor superfamily receptors on lymphocytes surface may transduce signals that control the survival, proliferation, differentiation, and effector functions of these immune cells. Among the members of the tumor necrosis factor receptor superfamily, there are 4-1BB and OX40. Several clinical studies have been carried out targeting these molecules, with agonist monoclonal antibodies, and preclinical studies exploring their ligands and other experimental approaches. In this review, we discuss functional aspects of 4-1BB and OX40 costimulation, as well as the progress of its application in immunotherapies.
RESUMO
Surface functionalization of silica nanoparticles (SiO2NPs) has been considered as a promising strategy to develop target-specific nanostructures. However, finding a chemical functionalization that can be used as an active targeting moiety while preserving the nanoparticles colloidal stability in biological fluids is still challenging. We present here a dual surface modification strategy for SiO2NPs where a zwitterion (ZW) and a biologically active group (BAG) (amino, mercapto or carboxylic functionalities) are simultaneously grafted on the nanoparticles' surface. The rationale behind this strategy is to generate colloidally stable nanoparticles and avoid the nonspecific protein adsorption due to ZW groups insertion, while the effective interaction with biosystems is guaranteed by the BAGs presence. The biological efficacy was tested against VERO cells, E. coli bacteria and Zika viruses and a similar trend was observed for all tested particles. The desirable "stealth property" to prevent nonspecific protein adhesion also generated a ZW shielding effect of the BAG functionality hindering their proper interaction and activity in cells, bacteria and viruses.
