Dendritic cells (DCs) are rare leukocytes that are uniquely potent in their recent
application to therapeutic cancer vaccines. Isolated DCs loaded with tumour
antigen ex vivo and administered as a cellular vaccine have been found to induce
protective and therapeutic anti-tumour immunity. In the present report we
describe the most common methods of culturing DCs and delivering tumour
antigens and we summarise clinical trials of cancer immunotherapy using DCs-based vaccines

Roliński, Jacek

Tabarkiewicz, Jacek

Wojas, Kamila

English

Via Medica Journals

Folia Morphol. Vol. 62, No. 4, pp. 317–318Copyright © 2003 Via MedicaISSN 0015–5659www.fm.viamedica.pl R E V I E W  A R T I C L E317Dendritic cells in cancer immunotherapy— a short reviewKamila Wojas, Jacek Tabarkiewicz, Jacek RolińskiDepartment of Clinical Immunology, Medical University, Lublin, Poland[Received 17 September 2003; Accepted 23 October 2003]Dendritic cells (DCs) are rare leukocytes that are uniquely potent in their recentapplication to therapeutic cancer vaccines. Isolated DCs loaded with tumourantigen ex vivo and administered as a cellular vaccine have been found to in-duce protective and therapeutic anti-tumour immunity. In the present report wedescribe the most common methods of culturing DCs and delivering tumourantigens and we summarise clinical trials of cancer immunotherapy using DCs--based vaccines.key words: dendritic cells, tumour antigen, immunotherapyAddress for correspondence: Kamila Wojas, Department of Clinical Immunology, Medical University, ul. Jaczewskiego 8, 20–093 Lublin,Poland, e-mail: kamilawojas@poczta.onet.plINTRODUCTIONDendritic cells are regarded as the most potentantigen-presenting cells [7]. They possess an extraor-dinary capacity to capture and process antigen andcontain all that is needed to stimulate T cell immuni-ty, including high levels of major histocompatibilitycomplex, co-stimulatory and adhesion molecules [1].These properties, coupled with the fact that it is nowpossible to generate large number of functional DCsex vivo, have led to interest in the use of DCs-vac-cines to induce anti-tumor immunity [1, 7]. The prep-aration of DC-vaccines consists of a 3-stage process:the generation of immature DCs from different cellpopulations using various stimulators, delivering thetumour antigens and, finally, the administration ofvaccines to patients [4, 7].PREPARATION OF DENDRITICCELL-BASED VACCINESDendritic cells provide a variety of important fea-tures to generate an immune response, makingthem very attractive cells for the immunotherapyof cancer [2, 8]. A prerequisite for the use of DCs intherapy is the development of techniques to gen-erate large numbers of DCs in culture. We can iso-late DCs precursors from the blood by using densi-ty-based purification [4, 7]. Circulating immatureDC precursors represent less than 1% of the pe-ripheral blood mononuclear cells (PBMC). There isthe possibility of amplifying the circulating DCs by treat-ment donors with Flt3 ligand or GM-CSF [2, 7, 8].A more effective approach is to culture DCs fromeither non-proliferating CD14+ monocytes or pro-liferating CD34+ precursor cells [2, 4, 7]. CD14+monocytes can be differentiated into immaturedendritic cells by culture with IL-4 and GM-CSF,whereas the protocols to produce DCs from CD34+cells include additional cytokines, such as SCF, Flt3and TNF-a [7, 8]. Another method of generatingDCs is the use of calcium ionophore (CI), which in-duces a very rapid differentiation from CD34+ cells,CD14+ monocytes as well as CML-progenitor cellsto mature DCs [7].The next step in the preparation of DC-vaccinesis to stimulate dendritic cells by tumour antigen. Theloading of antigen to dendritic cells can be achievedby several approaches. Many studies have used syn-thetic peptides as antigens such as Mage-1, Mage-3,gp-100 and MUC-1 [2, 7]. The advantage of this ap-proach is a well-defined antigen, which reduces thepossibility of autoimmunity and cross-reactivity andfacilitates in vitro and in vivo monitoring [7]. Due tothe fact that only a few tumour-specific antigens havebeen identified, strategies using the whole antigen318Folia Morphol., 2003, Vol. 62, No. 4array of the tumour cells have been explored: DCscan be fed tumour lysates or acid-eluted peptide mix-tures [2, 7, 8]. Several studies have used apoptotictumour cells as an antigen source [7]. The immuno-genicity of DCs pulsed with apoptotic tumour cellscan be improved by cytokines to improving the func-tion of DCs (TNF-a, IL-1, IL-6 or CD40L) [7]. The roleof necrotic cells as a source of antigen for DCs re-mains controversial. Some investigations have shownthat necrotic cells are needed for complete matura-tion of DCs and therefore provide an obligatory sig-nal to DCs internalising apoptotic tumour cells [7].A different strategy for using the whole tumour cellis the use of DC-tumour hybrids, generated by elec-trofusion or polyethylene glycol (PEG) treatment [2,4]. So far allogeneic and autologous DC-tumour hy-brids have been used in clinical trials. A new methodof delivering tumour antigens is to insert the genesencoding the tumour-associated antigen (TAA) intoDCs [7]. As vectors the most commonly used are retro-viral and adenoviral vectors, rarely pox viruses and her-pes viruses [7]. In some instances cationic lipids andplasmid-coated gold particles serve as non-viral vec-tors [7]. Another possibility is to pulse dendritic cellswith tumour-derived mRNA. In the human in vitro sys-tem, RNA-pulsed DCs were as effective in eliciting an-tigen-specific responses as peptide-pulsed DCs [7, 8].Especially in haematological diseases such as CMLand AML, several groups have used DCs arising fromthe malignant cells [2, 7, 8]. Since the patologicalevent occurs in the DC precursor, DCs generated invitro or in vivo present the antigens of the tumourcells. It has been demonstrated that monocyte-de-rived DCs from CML-patients carry the characteristicBcr-Abl antigens and generate CML-specific cytotoxicresponses [7].CLINICAL TRIALSOF DENDRITIC CELL VACCINATIONMany clinical DCs vaccination studies have beeninitiated or completed. These have focused mostlyon solid tumours, such as melanoma, breast, ovari-an, renal and prostate cancers, because these tu-mour-associated antigens are far better defined thanin other tumour types [3, 5, 6]. A series of clinicaltrials is beginning in haematological malignanciessuch as lymphoma, multiple myeloma and chronicand acute myelogenous leukemia, where DCs arecultured from the malignant cells [3, 5]. The recenttherapy described includes glioma patients and gas-trointestinal patients [3, 6]. These trials have none-theless established the general safety and feasibilityof this approach, in addition to demonstrating clin-ical anti-tumour activity [3, 5, 6]. These results havesuggested a broad series of questions about manu-facturing DCs on a large scale or using tumour anti-gens regardless of patient haplotype. These issuesshould be addressed in future trials.REFERENCES1. Armstrong AC, Eaton D, Ewing JC (2001) Cellular im-munotherapy for cancer. BMJ, 323: 1289–1293.2. Avigan D (1999) Dendritic cells: development, func-tion and potential use for cancer immunotherapy.Blood Rev, 13: 51–64.3. Davis ID, Jefford M, Parente P, Cebon J (2003) Ratio-nal approaches to human cancer immunotherapy.J Leukoc Biol, 73: 3–29.4. Feuerstein B, Berger TG, Maczek C, Roder C, Schreiner D,Hirsch V, Haendle I, Leisgang W, Glaser A, Kuss O, Diep-gen TL, Schuler G, Schuler-Thurner B (2000) A methodfor the production of cryopreserved aliquots of anti-gen-preloaded, mature dendritic cells ready for clini-cal use. J Immunol Methods, 245: 15–29.5. Guermonprez P, Valladeau J, Zitvogel L, Thery C,Amigorena S (2002) Antigen presentation and T cellstimulation by dendritic cells. Annu Rev Immunol,20: 621–667.6. Lotze MT (2001) Dendritic cells: second edition. Biolo-gy and clinical applications. Academic Press, UK.7. Meidenbauer N, Andreesen R, Mackensen A (2001)Dendritic cells for specific cancer immunotherapy. BiolChem, 382: 507–520.8. Timmerman JM, Levy R (1999) Dendritic cell vaccinesfor cancer immunotherapy. Annu Rev Med, 50: 507––529.

Dendritic cells in cancer immunotherapy - a short review

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Dendritic cells in cancer immunotherapy - a short review

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