Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells—An Update

Abstract

Over the last two decades, dendritic cell (DC) vaccination has been studied extensively as active immunotherapy in cancer treatment and has been proven safe in all clinical trials both with respect to short and long-term side effects. For antigen-loading of dendritic cells (DCs) one method is to introduce mRNA coding for the desired antigens. To target the whole antigenic repertoire of a tumor, even the total tumor mRNA of a macrodissected biopsy sample can be used. To date, reports have been published on a total of 781 patients suffering from different tumor entities and HIV-infection, who have been treated with DCs loaded with mRNA. The majority of those were melanoma patients, followed by HIV-infected patients, but leukemias, brain tumors, prostate cancer, renal cell carcinomas, pancreatic cancers and several others have also been treated. Next to antigen-loading, mRNA-electroporation allows a purposeful manipulation of the DCs’ phenotype and function to enhance their immunogenicity. In this review, we intend to give a comprehensive summary of what has been published regarding clinical testing of ex vivo generated mRNA-transfected DCs, with respect to safety and risk/benefit evaluations, choice of tumor antigens and RNA-source, and the design of better DCs for vaccination by transfection of mRNA-encoded functional proteins.

Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy

“…A fundamental breakthrough was the discovery that monocytes can be differentiated in the presence of granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4 ex vivo to moDCs at high numbers making DCs accessible for immunotherapeutic approaches [ 17 , 18 , 631 , 632 , 633 ]. To allow for the induction of immune responses, maturation of moDCs is a prerequisite.…”

“…To allow for the induction of immune responses, maturation of moDCs is a prerequisite. This can be achieved by different strategies including the treatment of moDCs with agonistic αCD40 antibodies, the application of TLR ligands or via usage of the classical moDCs maturation cocktail including IL-1β, IL-6, TNFα, and Prostaglandin E2 (PGE 2 ) [ 109 , 631 , 634 , 635 , 636 , 637 , 638 ]. Before adoptive transfer, moDCs can be loaded with antigen(s) of choice.…”

Network and systems based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy

“…All of these pathways had positive enrichment scores, indicating that the involved genes tended to be upregulated in caIKK-DCs according to our analysis. Most protein-coding genes used as indicators of DC activation and maturation (2,53,56,57) were found to be upregulated in the enriched pathways (Supplementary Table S8). The activation of NF-κB signalling led to upregulation of surface proteins that can prime T cells (e.g., CD40, CD70, CD80, and CD86), chemokines (e.g., CCL3 and CXCL10) that are necessary for T-cell migration, TNF superfamily members that can induce crosstalk between T cells and DCs (e.g., TNF, TNFRSF4, and TNFSF9), and cytokines that are responsible for stimulating proliferation and activation of T cells (e.g., CXCL8, IL6,…”

“…Dendritic cells (DCs) play an important role in regulating adaptive immunity by presenting antigens to T cells (1). Due to the unique function of DCs in the coordination of adaptive immune responses, they have been tested as cell-based vaccination against tumours (2). To obtain immunogenic potency ex vivo, monocyte-derived DCs need to go through a complex maturation process, in which DCs are exposed to a monocyte-conditioned medium or a cocktail of cytokines (3,4).…”

Kombination von Chemotherapie und autologen, Peptid‐beladenen dendritischen Zellen bringt Überlebensvorteil bei Melanompatienten im Stadium IV

“…In der Tat gibt es bereits einige wenige solcher Studien, allerdings noch mit bescheidenen Erfolgen [14,46]. Auf jeden Fall unterstreicht das, dass die weitere Optimierung der aktuellen DZ‐Vakzinationsprotokolle, speziell im Hinblick auf DZ‐Züchtung, Verabreichung (zum Beispiel „Targeting“ von Antigen an definierte Untergruppen von DZ [47–50]) und Formulierung der Antigene absolut notwendig ist. Dendritische Zellen werde auch in Zukunft ein wichtiger Bestandteil im (immun)therapeutischen Armamentarium gegen Krebs bleiben.…”