ReviewRNA pulsed dendritic cells: An approach for cancer immunotherapy
Graphical abstract
Highlights
► RNA pulsed DC: an improved therapeutic intervention for treating cancers. ► RNA transfections are advantageous over DNA transfection for cancer therapeutics. ► Engineered pH sensitive liposomes improved RNA transfection and sustained expression of tumor antigen.
Section snippets
Background
Immunotherapy for cancer remains one of the most debatable fields in hematology and oncology [1]. On one hand, hints exist that the immune system has the potential to effectively eradicate cancer cells as it happens in the graft versus leukemia effect or as it is observed in those cases of spontaneous tumor regressions reported in melanoma and renal cell carcinoma [2]. On the other hand, skepticism that such anti-tumor immunity can be elicited and exploited therapeutically has been fomented by
Immune surveillance and dendritic cell biology
The immune system has three major roles in the prevention of tumors. First, the immune system can defend the host from virus-induced tumors by eliminating or suppressing viral infections. Second, the timely appropriate elimination of pathogens and prompt resolution of inflammation can prevent the establishment of an inflammatory environment helpful to tumorigenesis. Third, the immune system can particularly identify and eliminate tumor cells on the basis of their expression of tumor-specific
Selection of the antigen for ex vivo loading of dendritic cells
DCs must be engineered for their phenotypic alterations with tumor antigens in order to elicit robust immune response against cancer cells in vaccinated patients. These antigens may be of various kinds such as peptides, cellular extracts from tumor cells, apoptotic bodies, purified proteins, or nucleic acids [57], [58], [59], [60]. These antigens, after being processed and then presented on the surface of DCs, are termed as defined antigenic peptides, which lead to the activation of
RNA based vaccines
The first vaccine approach, of simply attenuated pathogens, yielded considerable success for some diseases, however, carries the risk of inadvertent infection in the situation of insufficient attenuation of pathogens. The characterization of pathogen- or tumor-associated antigens by the molecular cloning techniques has opened new ways for the development of recombinant vaccines. The antigen of interest has been delivered to the host by a carrier (such as virus or bacteria), with limited side
Problems associated with “naked” RNA immunization
The main disadvantage of using naked RNA as a vaccine is the rapid degradation by omnipresent RNAses. Therefore, large quantities of RNA-vaccine have to be injected to circumvent the degradation problem and to deliver sufficient amount of RNA molecules into transfected cells and consequently, naked RNA vaccines would be a poor choice [76] as vaccines for weakly immunogenic tumor antigens, which require a potent immune response capable of breaking tolerance to non-mutated “self”-epitopes. mRNA
Phenotypically altered dendritic cells as cancer vaccines and immune response to vaccination
Immunosurveillance of tumor cells by the cellular immune system is often inefficient in vivo, which in turn reflected in the outgrowth of tumors and are apparently unable to provoke an immune response. Tumor cells are unable to prime anti-tumor T cells, because (1) inability of the tumor cells to provide the necessary co-stimulatory signals for T cell activation, (2) insufficient expression of antigenic determinants observed by the immune system, (3) secretion of some inhibitory factors such as
Routes of dendritic cells administration
So far, no general rule on how ex vivo generated DCs should be re-infused to the patients exists. Intradermal, subcutaneous, intravenous, and intranodal DC injections have all been performed in clinical trials [4], [5], [6] (Table 1). Besides, as mentioned before, intratumor DC injection has also been used. Some evidence suggests that intradermal and intranodal administration of antigen-loaded DCs may be more effective for the induction of an immune response [95], [96]. The injection into lymph
Clinical trials of mRNA-based vaccination against tumors
Some clinical trials data are published for tumor vaccination using mRNA including both direct vaccination and DC based vaccination in Table 1 [90], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114]. A clinical trial was published by Heiser et al. in 2001 in which they reported adoptive transfer of prostate specific antigen (PSA) mRNA-transfected autologous DCs in patients with prostate cancer [114]. Since then, a diversity of phase
Expert commentary and future perspectives
Different methods for DC culture, antigen loading, and administration have been used in the phase I and II of clinical studies. It is evident that ex vivo generated APCs are immunogenic in vivo and DC injection is clinically safe. However, the clinical advantages of DC vaccination is yet to be fully explored, phase III studies are necessary and are already on going for some disorders, such as melanoma and prostate cancer. A major limitation to immunotherapy development lies in the lack of
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These authors contributed equally to this work.