Harnessing Dendritic Cells for Poly (D,L-lactide-co-glycolide) Microspheres (PLGA MS)—Mediated Anti-tumor Therapy

Abstract

With emerging success in fighting off cancer, chronic infections, and autoimmune diseases, immunotherapy has become a promising therapeutic approach compared to conventional therapies such as surgery, chemotherapy, radiation therapy, or immunosuppressive medication. Despite the advancement of monoclonal antibody therapy against immune checkpoints, the development of safe and efficient cancer vaccine formulations still remains a pressing medical need. Anti-tumor immunotherapy requires the induction of antigen-specific CD8+ cytotoxic T lymphocyte (CTL) responses which recognize and specifically destroy tumor cells. Due to the crucial role of dendritic cells (DCs) in initiating anti-tumor immunity, targeting tumor antigens to DCs has become auspicious in modern vaccine research. Over the last two decades, micron- or nanometer-sized particulate delivery systems encapsulating tumor antigens and immunostimulatory molecules into biodegradable polymers have shown great promise for the induction of potent, specific and long-lasting anti-tumor responses in vivo . Enhanced vaccine efficiency of the polymeric micro/nanoparticles has been attributed to controlled and continuous release of encapsulated antigens, efficient targeting of antigen presenting cells (APCs) such as DCs and subsequent induction of CTL immunity. Poly (D, L-lactide- co -glycolide) (PLGA), as one of these polymers, has been extensively studied for the design and development of particulate antigen delivery systems in cancer therapy. This review provides an overview of the current state of research on the application of PLGA microspheres (PLGA MS) as anti-tumor cancer vaccines in activating and potentiating immune responses attempting to highlight their potential in the development of cancer therapeutics.

Polymeric Nanoparticles Containing Both Antigen and Vitamin D3 Induce Antigen-Specific Immune Suppression

“…Polymeric nanoparticles (NPs) generated from a biodegradable and biocompatible polymer, poly(D,L-lactide-co-glycolide) (PLGA), have been extensively explored as implantable reservoirs for sustained-release drug delivery. PLGA NPs have also been studied as vehicles for the delivery of antigens to phagocytes (15-18). PLGA NPs containing both antigens and drugs have remarkable advantages because they can specifically deliver the antigens and the drugs to phagocytes, such as DCs and macrophages, thereby reducing the potential systemic side effects of the drugs (19,20).…”

Targeted Co-delivery of Tumor Antigen and α-Galactosylceramide to CD141+ Dendritic Cells Induces a Potent Tumor Antigen-Specific Human CD8+ T Cell Response in Human Immune System Mice

“…The immunization regimens were selected based on our previously published studies ( 12 ), in which a free α-GalCer/tumor peptides complex, NP/α-GalCer/tumor peptides/IgG, and NP/α-GalCer/tumor peptides/anti-Clec9a were immunized 3 times and tumor-specific mouse CD8+ T-cell response, as well as α-GalCer-reactive mouse iNKT-cell response, were measured ( 12 ). Regimens were administered by the intramuscular route, because this route is one of the three parenteral routes (subcutaneous, intradermal, and intramuscular) approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for licensed PLGA to be used in humans ( 11 ). Therefore, in order to test the immunogenicity of the NP vaccine which co-delivers Melan A and α-GalCer and is decorated by anti-CLEC9A Ab (NP/Melan A/α-GalCer/anti-CLEC9A), a group of HIS-CD8/NKT mice were immunized three times i.m.…”

“…One well-studied approach is the use of poly(lactic-co-glycolic) acid (PLGA)-based nanoparticles (NP) as a vaccine delivery system. These NPs have several desired properties, including high antigen density, incorporation of different classes of molecules including proteins and lipids, ability to reach the MHC-class I pathway after uptake by dendritic cells (DCs), and slow extended release of their payload ( 10 , 11 ). PLGA-based NP vaccines can also be targeted to specific cell types; for example, to CD141 + (BDCA3 + ) cross-priming DCs by using anti-CLEC9A antibodies (Abs) ( 12 ).…”

Hitchhiking on Controlled-Release Drug Delivery Systems: Opportunities and Challenges for Cancer Vaccines

“…Peris and Langer proposed in 1979 for the first time that the release of antigens could be controlled using polymeric materials to stimulate immune responses (Peris and Langer, 1979). Numerous natural and synthetic biodegradable polymeric materials including chitosan, alginate, gelatin, poly(lactic-coglycolic acid) (PLGA), Poly(lactic acid) (PLA), poly(εcaprolactone) (PCL), poly(β-amino esters) (PBAE) and poly(methyl methacrylate) (PMMA), etc., as well as some inorganic materials (such as silica) have been widely used in the field of controlled release of antigens and immunomodulatory agents (Lin et al, 2015;Zhu et al, 2018;Huang et al, 2019;Koerner et al, 2019;Hou et al, 2021). Polymeric microparticles (MPs) or microspheres can induce potent antigen-specific immunity by controlling the release of antigens or mimicking the size of pathogens, but they are much safer than live pathogens (Huang et al, 2019).…”

“…By modulating the polymer molecular weight, composition, preparation method, particle size and additives, etc., MPs can provide sustained or pulsatile release of entrapped antigens over periods lasting weeks to months (Sivakumar et al, 2011). Furthermore, the modification of surface physicochemical properties or decoration with ligands or antibodies can lead to different functionalized MPs (Figure 2), such as APCs-targeting MPs, immune cell-engaging particles (artificial DCs) or MPs for intranasal vaccination (Mata et al, 2011;Li et al, 2016b;Jung et al, 2019;Koerner et al, 2019;Huang et al, 2020). Among the most extensively exploited synthetic polymers in many areas, PLGA has been approved by the FDA for human use in drug delivery and biomedical devices due to its biodegradability and biocompatibility (Koerner et al, 2019).…”