Recently, the Islam A. Khalil research team of Misr University of Science and Technology in Egypt published a review titled "Cancer immunotherapy from biology to nanomedicine" in the Journal of Controlled Release, Issue 336, 2021.
Cancer is one of the leading causes of human death, and treatments such as chemotherapy, radiotherapy and surgery all have their therapeutic limitations. Immunotherapy is a new and promising therapeutic approach that has developed rapidly in the last decade. Immunotherapeutic agents help immune cells recognize and engage tumor cells by acting on tumor-specific pathways, antigens or cellular targets, and they have been shown to eradicate tumor cells and avoid multidrug resistance (MDR) with fewer side effects than conventional cytotoxic therapies.
Immunotherapeutic drugs can be broadly classified into four types: checkpoint inhibitors, cytokines, monoclonal antibodies, and vaccines. However, immunotherapeutic drugs still have some problems, such as off-target side effects and poor pharmacokinetics. Nanomedicine can address some of the limitations of current immunotherapies, such as local delivery, controlled release, and enhanced pharmacokinetics. In this review, the authors describe each of these immunotherapeutic agents and nanomedicine approaches to further improve their efficacy and safety.
Immune checkpoints are regulators of the immune system that maintain self-tolerance. They regulate the immune response against foreign antigens to prevent damage to surrounding healthy tissues and prevent immune cells from mistakenly attacking their own cells. Immune checkpoints include the tumor necrosis receptor family (TNFRs) and the immunoglobulin superfamily (IgSF), which activate T cells, as well as the CTLA 4 receptor and the programmed death ligand-1 (PD-L1) receptor, which inhibit T cell activation.
Cancer cells generate immune resistance by dysregulating immune checkpoints in order to bypass recognition and attack by the immune system. Immune checkpoint inhibitors enhance the killing effect of the immune system on tumor cells by inhibiting these regulatory pathways activated by tumor cells (Figure 1).
Figure 1. Checkpoint Inhibitors are promising immunotherapies that trigger anti-tumor immunity. For example, CTLA-4, PD-1 and PD-L1 antibodies are already approved for clinical use.
Although immune checkpoint inhibitors have shown promising efficacy in a variety of cancers, they also have some side effects. Nanotechnology can overcome the problems caused by the non-specific property of immune checkpoint inhibitors by providing targeted delivery, reducing side effects and enhancing efficacy.
Cytokines were the first FDA-approved cancer immunotherapeutic agents. There are three main classes of cytokines used in the clinical treatment of cancer: interleukins (ILs), interferons (IFNs) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Cytokine therapy has great potential in cancer immunotherapy, but the main problem that hinders its development is the potential for a "cytokine storm" when administered systemically. At the same time, cytokines have a short half-life in plasma due to rapid enzymatic degradation and clearance, and have a strong off-target effect. To compensate for their short half-life, systemic administration of cytokines requires relatively large doses, which can lead to acute toxic effects.
Figure 2. Diagram of cytokine delivery
Nanoparticles can deliver cytokines to specific tissues and release them continuously for hours or even days with less adverse effects on healthy tissues. The two most established nanocarriers are liposomal and polymer-based nanocarriers, which have been used as delivery systems for cytokines such as IFN-α, IFN-β, IFN-γ, IL-2, IL-12, leukemia inhibitory factor (LIF), etc. The cycle time of liposomes and polymeric nanoparticles can be greatly increased by their modification with polyethylene glycol on their surface. The addition of certain sugars and surfactants to the buffer can improve the stability of IFN-γ during the encapsulation process. In addition, biomimetic modifications can be performed, such as attaching cytokines to the surface of polymer particles, which can mimic the binding of natural cytokines to cell membranes. Magnetic nanoparticles and colloidal gold (cAu) nanoparticles have also been shown to deliver cytokines.
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Monoclonal antibodies (mAb)
The use of monoclonal antibodies (mAb) in cancer therapy is well established, with several FDA-approved drugs. mAb have three main mechanisms of action, including direct action of the antibody, immune-mediated cell killing, and blockade of angiogenesis at the tumor site (Figure 3). Among them, immune-mediated cell killing occurs through multiple mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and regulation of T-cell function.
Figure 3. Three different mechanisms by which antibodies eradicate cancer cells
The efficacy of mAb therapy may be limited by poor pharmacokinetics, limited distribution to tumor tissue, and poor bioavailability. These limitations are related to the biological nature of mAb, first-pass effects, and degradation by different proteases in vivo. The use of nanocarriers as delivery vehicles for mAb can protect mAb from degradation, selectively enhance its uptake in tumor tissues and improve pharmacokinetics and tissue distribution. Nanocarriers that have been used for the delivery of mAb include gold nanoparticles (AuNPs), MNP-HC, PLGA nanocarrier systems, immunoliposomes (IL) and mesoporous silica nanoparticles (MSN).
Cancer vaccines can be divided into prophylactic and therapeutic vaccines. Typically, prophylactic vaccines target cancers that are caused by viral infections. Several prophylactic cancer vaccines have been approved by the FDA, such as Cervarix® and Gardasil-9® for the prevention of human papillomavirus (HPV). The development of therapeutic vaccines is based on three main directions, including the selection of tumor-associated antigens (TAA) and tumor-specific antigens (TSA) overexpressed in tumor cells, the construction of delivery systems to target tumor cells, and the selection of adjuvants to enhance the immune response. In addition, mRNA-based therapeutic vaccines can induce the generation of personalized immune responses against cancer cells and have strong application prospects.
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The design of the vaccine delivery system is critical to the success of a cancer vaccine. Viral, bacterial or yeast vectors have the advantage of delivering some or all of the tumor antigens or their genes, and several different tumor antigen genes can be delivered simultaneously with these vectors. In addition, nanoparticles have been widely used to deliver cancer vaccines, as they avoid degradation of the vaccine and enhance its pharmacokinetics. Also, nanoparticles can be functionalized for targeted delivery of vaccines by attaching targeting molecules to the surface of the nanoparticles (Figure 4). Nanoparticle carriers can also be designed to resemble the structure of pathogens (e.g., viruses) to further enhance the immune response and vaccination efficacy. Several nanoparticles have shown potential as cancer vaccine carriers, such as gold, silica, magnetic inorganic nanoparticles, and polymeric nanoparticles .
Figure 4. nanocarrier-encapsulated or surface-bound antigens
The next generation of cancer immunotherapies is focused on studying the tumor microenvironment and gaining insight into its immunosuppressive properties. In addition, a better understanding of tumor heterogeneity and various cancer-related biomarkers is needed in order to select the appropriate immunotherapy for different patient cases. Currently, these challenges are addressed by using different immunotherapeutic approaches in combination with nanomedicine vectors. However, there remains an imbalance between the efficiency and safety of these therapeutic approaches. Some immunotherapeutic approaches designed to target tumor microenvironment features, such as adoptive cell therapies (ACTs) and multifunctional antibodies, show potential as next-generation cancer immunotherapies.
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 Salma B. Abdelbaky, Mayar Tarek Ibrahim, Hebatallah Samy, Menatalla Mohamed, Hebatallah Mohamed, Mahmoud Mustafa, Moustafa M. Abdelaziz, M. Laird Forrest, Islam A. Khalil, Cancer immunotherapy from biology to nanomedicine, Journal of Controlled Release, Volume 336, 2021, Pages 410-432, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2021.06.025.
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