The use of dendritic cells in cancer immunotherapy

Current Opinion in Immunology

Volumn 15, Issue 2, 2003, Pages 138-147

  Schuler, Gerold ^a   Schuler Thurner, Beatrice ^a   Steinman, Ralph M ^b  

^a UNIVERSITY HOSPITAL ERLANGEN   (Germany)

^b ROCKEFELLER UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD14 ANTIGEN; CD32 ANTIGEN; CD34 ANTIGEN; CD40 ANTIGEN; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HLA ANTIGEN; INTERLEUKIN 12; INTERLEUKIN 13; INTERLEUKIN 15; INTERLEUKIN 1BETA; INTERLEUKIN 2; INTERLEUKIN 4; INTERLEUKIN 6; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 1; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; PROSTAGLANDIN E2; TUMOR ANTIGEN; TUMOR NECROSIS FACTOR ALPHA;

ANALYTIC METHOD; BIOLOGY; CANCER IMMUNOTHERAPY; CELL MATURATION; DENDRITIC CELL; HUMAN; IMMUNE RESPONSE; MEDICAL RESEARCH; REVIEW; VACCINATION;

EID: 0037375713     PISSN: 09527915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0952-7915(03)00015-3     Document Type: Review

References (74)

1. Dallal R.M., Lotze M.T. The dendritic cell and human cancer vaccines. Curr. Opin. Immunol. 12:2000;583-588.
2. Banchereau J., Schuler-Thurner B., Palucka A.K., Schuler G. Dendritic cells as vectors for therapy. Cell. 106:2001;271-274.
3. Steinman R.M., Dhodapkar M. Active immunization against cancer with dendritic cells: the near future. Int. J. Cancer. 94:2001;459-473.
4. + regulatory T cells and thus tolerance.
5. Roncarolo M.G., Levings M.K., Traversari C. Differentiation of T regulatory cells by immature dendritic cells. J. Exp. Med. 193:2001;F5-F9.
6. Josien R., Li H.L., Ingulli E., Sarma S., Wong B.R., Vologodskaia M., Steinman R.M., Choi Y. TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J. Exp. Med. 191:2000;495-502.
7. Liu K., Iyoda T., Saternus M., Kimura Y., Inaba K., Steinman R.M. Immune tolerance after delivery of dying cells to dendritic cells in situ. J. Exp. Med. 196:2002;1091-1097 This work provides yet another reason (see also [6]) to consider the viability of DCs used for vaccination as critical, because dying antigen-carrying DCs can be taken up by resident tolerogenic DCs.
8. Hsu F.J., Benike C., Fagnoni F., Liles T.M., Czerwinski D., Taidi B., Engleman E.G., Levy R. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat. Med. 2:1996;52-58.
9. Fong L., Hou Y., Rivas A., Benike C., Yuen A., Fisher G.A., Davis M.M., Engleman E.G. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc. Natl. Acad. Sci. USA. 98:2001;8809-8814 This study is interesting for several reasons. First, the induction of ex vivo detectable CEA-specific effector CTLs is unequivocally demonstrated by multicolor tetramer staining, second, the induced CTL responses directly correlate with clinical responses.
10. Shortman K., Liu Y.J. Mouse and human dendritic cell subtypes. Nat. Rev. Immunol. 2:2002;151-161.
11. Gatti E., Velleca M.A., Biedermann B.C., Ma W., Unternaehrer J., Ebersold M.W., Medzhitov R., Pober J.S., Mellman I. Large-scale culture and selective maturation of human Langerhans cells from granulocyte colony-stimulating factor-mobilized CD34+ progenitors. J. Immunol. 164:2000;3600-3607.
12. ••].
13. 2, as a maturation stimulus for DCs.
14. Berger T.G., Feuerstein B., Strasser E., Hirsch U., Schreiner D., Schuler G., Schuler-Thurner B. Large-scale generation of mature monocyte-derived dendritic cells for clinical application in cell factories. J. Immunol. Methods. 268:2002;131-140 In this manuscript, the authors describe their extensive experience of using 'cell factories' manufactured by Nunc (a multilayered communicating closed culture vessel offering a surface big enough to cultivate one leukapheresis product) for the standardized production of Mo-DCs for clinical application. In addition, the data (yield, phenotype etc.) provided are based on a large number of processed leukaphereses and are thus meaningful for establishing validation criteria.
15. Tuyaerts S., Noppe S.M., Corthals J., Breckpot K., Heirman C., De Greef C., Van Riet I., Thielemans K. Generation of large numbers of dendritic cells in a closed system using Cell Factories. J. Immunol. Methods. 264:2002;135-151 These authors demonstrate that the Mo-DCs generated in Nunc 'cell factories' display identical properties to those prepared in standard tissue culture vessels.
16. Feuerstein B., Berger T.G., Maczek C., Roder C., Schreiner D., Hirsch U., Haendle I., Leisgang W., Glaser A., Kuss O.et al. A method for the production of cryopreserved aliquots of antigen-preloaded, mature dendritic cells ready for clinical use. J. Immunol. Methods. 245:2000;15-29.
17. Pullarkat V., Lau R., Lee S.M., Bender J.G., Weber J.S. Large-scale monocyte enrichment coupled with a closed culture system for the generation of human dendritic cells. J. Immunol. Methods. 267:2002;173-183.
18. ••].
19. ••] describe examples of the use of monoclonal antibodies to MHC-peptide complexes, which were selected from phage display libraries and in vitro affinity matured for enhanced binding to allow flow cytometric detection of MHC-peptide complexes. These reagents should prove valuable for the validation of DC vaccines, and also for an investigation of the relationship between MHC-peptide complex density and the quantity as well as quality of induced T-cell responses.
20. van der Burg S.H., Visseren M.J., Brandt R.M., Kast W.M., Melief C.J. Immunogenicity of peptides bound to MHC class I molecules depends on the MHC-peptide complex stability. J. Immunol. 156:1996;3308-3314.
21. Banchereau J., Palucka A.K., Dhodapkar M., Burkeholder S., Taquet N., Rolland A., Taquet S., Coquery S., Wittkowski K.M., Bhardwaj N.et al. Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res. 61:2001;6451-6458 This clinical trial is particularly interesting, as clinical regressions occurred during the study, which correlated with induced immune responses to four melanoma antigens. Remarkably, the latter were not only detectable after re-stimulation of T cells, but also directly ex vivo.
22. Palmowski M.J., Choi E.M., Hermans I.F., Gilbert S.C., Chen J.L., Gileadi U., Salio M., Van Pel A., Man S., Bonin E.et al. Competition between CTL narrows the immune response induced by prime-boost vaccination protocols. J. Immunol. 168:2002;4391-4398 This work unravels a potential complication when an APC simultaneously presents several immunodominant epitopes, in that only those CTL precursors present at the highest frequency are expanded. These findings have to be taken into account in the rational design of vaccines.
23. Wang R.F., Wang H.Y. Enhancement of antitumor immunity by prolonging antigen presentation on dendritic cells. Nat. Biotechnol. 20:2002;149-154 This paper is a direct demonstration that the short half-life of MHC-peptide complexes formed upon peptide pulsing is improved through loading DCs from the inside using a peptide linked to a cell-penetrating peptide. This technique also results in enhanced immunogenicity, which is important for optimizing DC vaccines.
24. Gnjatic S., Atanackovic D., Matsuo M., Sager E.J., Chen Y.T., Ritter G., Knuth A., Old L.J. Cross-presentation of HLA class I epitopes from exogenous NY-ESO-1 polypeptides by non-professional antigen presenting cells. J. Immunol. 170:2003;1191-1196 The authors find that long 30mer peptides enter APCs, and are processed to short peptides leading to the formation of MHC class I-peptide complexes at the cell surface.
25. ••]) are highly relevant.
26. Berlyn K.A., Schultes B., Leveugle B., Noujaim A.A., Alexander R.B., Mann D.L. Generation of CD4(+) and CD8(+) T lymphocyte responses by dendritic cells armed with PSA/anti-PSA (antigen/antibody) complexes. Clin. Immunol. 101:2001;276-283 The authors describe that loading of Mo-DCs with immune complexes leads to the formation of MHC class II and, via cross-presentation, also MHC class I complexes, whereas soluble protein only yields MHC class II-peptide complexes, as expected. The loading of antigens via Fc receptors thus allows DCs to induce both helper and cytotoxic T cells.
27. + DCs are capable of cross-presentation upon uptake of NY-ESO-1-antibody complexes.
28. ••].
29. ••] independently, and by using different knockout mice to impair the inhibitory Fc receptors, show that loading murine DCs with immune complexes through the selective engagement of activating Fc receptors leads to a dramatic improvement of DC-based vaccination.
30. Nair S.K., Boczkowski D., Morse M., Cumming R.I., Lyerly H.K., Gilboa E. Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA. Nat. Biotechnol. 16:1998;364-369.
31. Van Tendeloo V.F., Ponsaerts P., Lardon F., Nijs G., Lenjou M., Van Broeckhoven C., Van Bockstaele D.R., Berneman Z.N. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood. 98:2001;49-56 The authors describe a method to reproducibly electroporate RNA into DCs as a substitute for the variable and inefficient loading with naked RNA.
32. + T-cell responses in vitro.
33. Kugler A., Stuhler G., Walden P., Zoller G., Zobywalski A., Brossart P., Trefzer U., Ullrich S., Muller C.A., Becker V.et al. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nat. Med. 6:2000;332-336.
34. + T lymphocyte responses. Blood. 96:2000;1857-1864.
35. + T cells for efficient tumor cell lysis. Cancer Res. 60:2000;4446-4452.
36. Berard F., Blanco P., Davoust J., Neidhart-Berard E.M., Nouri-Shirazi M., Taquet N., Rimoldi D., Cerottini J.C., Banchereau J., Palucka A.K. Cross-priming of naïve CD8 T cells against melanoma antigens using dendritic cells loaded with killed allogeneic melanoma cells. J. Exp. Med. 192:2000;1535-1544.
37. + IFN-γ-producing T cells from tumor-infiltrating lymphocytes. J. Immunol. 164:2000;6633-6639.
38. Dhodapkar M.V., Krasovsky J., Olson K. T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells. Proc. Natl. Acad. Sci. USA. 99:2002;13009-13013 This is a remarkable manuscript as it not only shows that DCs loaded with antibody-coated autologous myeloma cells are effective in inducing tumor-specific CTLs but also that these CTLs are specific for the 'fresh' tumor cells of the patient and recognize cultured myeloma cells less efficiently. This indicates that patient-specific antigens are relevant, and that it might be important to use fresh tumor cells rather than tumor cell lines or defined antigens as a source of tumor antigens for successful vaccination against certain cancers.
39. Boczkowski D., Nair S.K., Nam J.H., Lyerly H.K., Gilboa E. Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells. Cancer Res. 60:2000;1028-1034.
40. Lanzavecchia A. Immunology. Licence to kill. Nature. 393:1998;413-414.
41. Thurner B., Haendle I., Roder C., Dieckmann D., Keikavoussi P., Jonuleit H., Bender A., Maczek C., Schreiner D., von den Driesch P.et al. Vaccination with Mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J. Exp. Med. 190:1999;1669-1678.
42. Fong L., Brockstedt D., Benike C., Wu L., Engleman E.G. Dendritic cells injected via different routes induce immunity in cancer patients. J. Immunol. 166:2001;4254-4259 In this clinical trial, evidence is provided that the cutaneous route of DC vaccination might promote Th1 immunity.
43. Schuler-Thurner B., Schultz E.S., Berger T.G., Weinlich G., Ebner S., Woerl P., Bender A., Feuerstein B., Fritsch P.O., Romani N., Schuler G. Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J. Exp. Med. 195:2002;1279-1288 In this paper, it is shown for the first time that mature, peptide-loaded DCs are capable of rapidly inducing Th1 cells (both ex vivo effectors and proliferating precursors) specific for a tumor antigen, specifically several Mage-3 peptides.
44. Nestle F.O., Alijagic S., Gilliet M., Sun Y., Grabbe S., Dummer R., Burg G., Schadendorf D. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat. Med. 4:1998;328-332.
45. ••]).
46. Robbiani D.F., Finch R.A., Jager D., Muller W.A., Sartorelli A.C., Randolph G.J. The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3beta, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell. 103:2000;757-768.
47. Ludewig B., Odermatt B., Landmann S., Hengartner H., Zinkernagel R.M. Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue. J. Exp. Med. 188:1998;1493-1501.
48. + T cell-dependent elimination of dendritic cells in vivo limits the induction of antitumor immunity. J. Immunol. 164:2000;3095-3101.
49. Schrama D., Pederson L.O., Keikavoussi P., Andersen M.H., thor Straten P., Bröcker E.B., Kämpgen E., Becker J.C. Aggregation of antigen-specific T cells at the inoculation site of mature dendritic cells. J. Invest. Dermatol. 119:2002;1443-1448 The authors use novel in situ tetramer staining and find that at the inoculation site of vaccination with mature DCs, antigen-specific T cells get trapped. This trapping of T cells and DCs might be disadvantageous, as the proportion of DCs migrating to the regional lymph nodes will be diminished.
50. Dhodapkar M.V., Krasovsky J., Steinman R.M., Bhardwaj N. Mature dendritic cells boost functionally superior CD8(+) T-cell in humans without foreign helper epitopes. J. Clin. Invest. 105:2000;R9-R14.
51. + melanoma patients by mature monocyte-derived dendritic cells. J. Immunol. 165:2000;3492-3496.
52. Andersen M.H., Keikavoussi P., Brocker E.B., Schuler-Thurner B., Jonassen M., Sondergaard I., Straten P.T., Becker J.C., Kämpgen E. Induction of systemic CTL responses in melanoma patients by dendritic cell vaccination: cessation of CTL responses is associated with disease progression. Int. J. Cancer. 94:2001;820-824 Because of the possibility of immune escape, the induction of tumor immunity might not always correlate with clinical regressions. In this paper, the reverse approach is taken, that is, it is observed that following stabilization disease progression occurs upon exhaustion of an anti-tumor response.
53. Birmingham K. Misconduct trouble brewing in Göttingen. Nat. Med. 7:2001;875 This work questions the reported clinical regressions that caused so much interest following the publication of [33].
54. Höltl L., Zelle-Rieser C., Gander H., Papesh C., Ramoner R., Bartsch G., Rogatsch H., Barsoum A.L., Coggin J.H. Jr., Thurnher M. Immunotherapy of metastatic renal cell carcinoma with tumor lysate-pulsed autologous dendritic cells. Clin. Cancer Res. 8:2002;3369-3376 This clinical trial protocol is somewhat heterogeneous (e.g. large variations in the number of tumor lysate-pulsed DCs administered etc.), but the rate of clinical regressions is of interest, as is the demonstration of T-cell responses to oncofetal antigen (immature laminin receptor), which might be an interesting antigen to look at in further studies.
55. Fong L., Brockstedt D., Benike C., Breen J.K., Strang G., Ruegg C.L., Engleman E.G. Dendritic cell-based xenoantigen vaccination for prostate cancer immunotherapy. J. Immunol. 167:2001;7150-7156 In an interesting approach, the authors used mouse PAP xenoantigen to load DCs and circumvent the low immunogenicity of tolerance to human PAP.
56. Small E.J., Fratesi P., Reese D.M., Strang G., Laus R., Peshwa M.V., Valone F.H. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J. Clin. Oncol. 18:2000;3894-3903.
57. Burch P.A., Breen J.K., Buckner J.C., Gastineau D.A., Kaur J.A., Laus R.L., Padley D.J., Peshwa M.V., Pitot H.C., Richardson R.L.et al. Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. Clin. Cancer Res. 6:2000;2175-2182.
58. Dendreon Corporation: Dendreon announces preliminary analysis of its first Phase III Provenge™ trial. URL: http://www.dendreon.com, News and Events, August 9, 2002.
59. + T cell responses, are reported.
60. Brossart P., Wirths S., Stuhler G., Reichardt V.L., Kanz L., Brugger W. Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood. 96:2000;3102-3108.
61. Klenerman P., Cerundolo V., Dunbar P.R. Tracking T cells with tetramers: new tales from new tools. Nat. Rev. Immunol. 2:2002;263-272.
62. •].
63. •] nicely illustrate the power of modern immunomonitoring techniques.
64. Ferlazzo G., Tsang M.L., Moretta L., Melioli G., Steinman R.M., Munz C. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J. Exp. Med. 195:2002;343-351 This manuscript demonstrates that mature Mo-DCs directly activate human NK cells, indicating that Mo-DCs might be utilized to activate the power of NK cells against cancer.
65. Fujii S., Shimizu K., Kronenberg M., Steinman R.M. Prolonged IFN-γ-producing NKT response induced with α-galactosylceramide-loaded DCs. Nat. Immunol. 3:2002;867-874 The authors demonstrate that α-galactosylceramide-loaded mature Mo-DCs activate NKT cells to release IFN-γ, but not IL-4. This suggests that such DCs will be useful for activating NKT cells in man for cancer immunotherapy, as this will avoid the unwanted IL-4 release by NKT cells, which might result from administration of soluble α-galactosylceramide alone.
66. Thery C., Zitvogel L., Amigorena S. Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2:2002;569-579.
67. Hawiger D., Inaba K., Dorsett Y., Guo M., Mahnke K., Rivera M., Ravetch J.V., Steinman R.M., Nussenzweig M.C. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194:2001;769-779 In this paper, it is shown that targeting of antigen to the DEC-205 endocytic molecule, which is constitutively expressed on the surface of certain lymph node DCs, results in deletion of antigen-specific T cells, whereas the simultaneous delivery of a DC-activating stimulus leads to immunity. As the DEC-205 molecule is also identified in humans, these findings open up a novel approach to manipulating immunity by targeting DCs directly in vivo.
68. Kirk C.J., Hartigan-O'Connor D., Mule J.J. The dynamics of the T-cell antitumor response: chemokine-secreting dendritic cells can prime tumor-reactive T cells extranodally. Cancer Res. 61:2001;8794-8802 This work provides an important proof of concept by showing that the injection of DCs into tumors can lead to immunity. This suggests that in the future one might be able to induce cancer resistance by guiding DCs to tumors and then activating them.
69. Dunbar P.R., Chen J.L., Chao D., Rust N., Teisserenc H., Ogg G.S., Romero P., Weynants P., Cerundolo V. Cutting edge: rapid cloning of tumor-specific CTL suitable for adoptive immunotherapy of melanoma. J. Immunol. 162:1999;6959-6962.
70. Dudley M.E., Wunderlich J.R., Robbins P.F., Yang J.C., Hwu P., Schwartzentruber D.J., Topalian S.L., Sherry R., Restifo N.P., Hubicki A.M.et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 298:2002;850-854 In this adoptive immunotherapy approach, high numbers of melanoma-specific T cells were administered after non-myeloablative chemotherapy (which, in addition to other side-effects, may also remove regulatory T cells) and were further expanded by i.v. IL-2 administration, resulting in impressive clinical regressions. This approach is not widely applicable, but provides important evidence that tumor-specific T cells can indeed mediate clinical regressions.
71. Shimizu K., Fields R.C., Giedlin M., Mule J.J. Systemic administration of interleukin 2 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines. Proc. Natl. Acad. Sci. USA. 96:1999;2268-2273.
72. •] demonstrate that it might be worthwhile to explore the combination of DC vaccination with IL-2 administration in man, as the T-cell responses induced by DC vaccination appear enhanced and therapeutically more effective.
73. + T-cell responses is augmented.
74. + regulatory T cells, which appear to suppress immune responses.