Elsevier

Vaccine

Volume 31, Issue 8, 6 February 2013, Pages 1141-1156
Vaccine

Review
RNA pulsed dendritic cells: An approach for cancer immunotherapy

https://doi.org/10.1016/j.vaccine.2012.12.027Get rights and content

Abstract

The immunotherapy of cancer is aimed at evoking both branches of immune system to elicite specific immune responses directed against tumor antigens to deal with residual tumor cells upon interaction, and thereby decreases mortality as well as morbidity of cancer patients. As dendritic cells (DCs) are specialized for antigen presentation, and their immunogenicity leads to the induction of antigen specific immune responses, various immunotherapeutic approaches have been designed for using DCs to present tumor-associated antigens to T-lymphocytes. As a part of proposed strategy ex vivo generated DCs might be loaded with antigens and re-infused to the patients and/or they can be used for the ex vivo expansion of anti-tumor lymphocytes. The DCs loaded ex vivo with RNA can be safely administered which proves to be an asset for producing antigen specific immune responses. Furthermore, already conducted studies have prompted clinical trials to be designed to investigate immunological and clinical effects of RNA pulsed DCs administered as an engineered therapeutic vaccine in cancer patients. However, selection of the antigens of interest, methods for introducing TAAgs into MHC class I and II processing pathways, methods for isolation and activation of DCs, and route of administration are the parameters to be considered for designing and conducting clinical trials with engineered DCs. The enhanced RNA transfection efficiency would further improve antigen processing and presentation and T-cell co-stimulation, resulting in the induction of heightened anti-tumor immune responses. Therefore, RNA transfected dendritic cells continue to hold promise for cellular immunotherapy and opens new avenues to devising further strategies for cancer therapeutic interventions.

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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