The use of dendritic cells in cancer immunotherapy.

Cancer immunotherapy aims at eliciting an immune response directed against tumor antigens to help fight off residual tumor cells and thereby improve survival and quality of life of cancer patients. Different immunotherapeutic approaches share the use of dendritic cells (DCs) to present tumor-associated antigens to T-lymphocytes. Ex vivo generated DCs can be loaded with antigens and re-infused to the patients, or they can be used for ex vivo expansion of antitumor lymphocytes. Alternatively, methods exist to target antigens to DCs in vivo without need for ex vivo cell manipulations. The clinical studies have shown that DC administration to patients is safe and induces antigen-specific immunity. However, it seldom elicits objective clinical responses in patients with advanced-stage malignancies. Novel insights into DC and lymphocyte regulation are expected to lead to more effective vaccines in the near future. Meanwhile, efforts are directed at identifying the most appropriate clinical targets for active specific immunotherapies. Data suggests that vaccinations may indeed be beneficial when given in the adjuvant setting rather than to treat metastatic cancers. These issues are discussed here together with an overview of the DC-based antitumor immunotherapy studies.

[1]  Hans-Georg Rammensee,et al.  Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. , 2002, Blood.

[2]  E. Gilboa,et al.  Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA , 1998, Nature Biotechnology.

[3]  F. Sallusto,et al.  Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha , 1994, The Journal of experimental medicine.

[4]  Steffen Jung,et al.  The Shiga toxin B‐subunit targets antigen in vivo to dendritic cells and elicits anti‐tumor immunity , 2006, European journal of immunology.

[5]  L. Liau,et al.  The TLR-7 Agonist, Imiquimod, Enhances Dendritic Cell Survival and Promotes Tumor Antigen-Specific T Cell Priming: Relation to Central Nervous System Antitumor Immunity1 , 2006, The Journal of Immunology.

[6]  R. Steinman,et al.  Glycolipid α-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice , 2006 .

[7]  A. Heine,et al.  Processing and presentation of HLA class I and II epitopes by dendritic cells after transfection with in vitro-transcribed MUC1 RNA. , 2005, Blood.

[8]  J. Loucká,et al.  Antigen Targeting to CD11b Allows Efficient Presentation of CD4+ and CD8+ T Cell Epitopes and In Vivo Th1-Polarized T Cell Priming1 , 2004, The Journal of Immunology.

[9]  C. Broeckhoven,et al.  Nonviral transfection of distinct types of human dendritic cells: high-efficiency gene transfer by electroporation into hematopoietic progenitor- but not monocyte-derived dendritic cells , 1998, Gene Therapy.

[10]  Sebastian Amigorena,et al.  In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor , 2007, The Journal of experimental medicine.

[11]  T. Kaisho,et al.  Dendritic-cell function in Toll-like receptor- and MyD88-knockout mice. , 2001, Trends in immunology.

[12]  L. Kanz,et al.  Tumor necrosis factor alpha and CD40 ligand antagonize the inhibitory effects of interleukin 10 on T-cell stimulatory capacity of dendritic cells. , 2000, Cancer research.

[13]  M. Akashi,et al.  Targeting of Antigen to Dendritic Cells with Poly(γ-Glutamic Acid) Nanoparticles Induces Antigen-Specific Humoral and Cellular Immunity1 , 2007, The Journal of Immunology.

[14]  D. Mahvi,et al.  A Phase I Study of Immunization Using Particle-Mediated Epidermal Delivery of Genes for gp100 and GM-CSF into Uninvolved Skin of Melanoma Patients , 2007, Clinical Cancer Research.

[15]  Gerold Schuler,et al.  Dendritic Cells as Vectors for Therapy , 2001, Cell.

[16]  Sai T Reddy,et al.  In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[17]  M. Noble,et al.  Cancer stem cells. , 2006, The New England journal of medicine.

[18]  S. Rosenberg,et al.  Cancer immunotherapy: moving beyond current vaccines , 2004, Nature Medicine.

[19]  A. Enk,et al.  Targeting of antigens to activated dendritic cells in vivo cures metastatic melanoma in mice. , 2005, Cancer research.

[20]  M. Hanna,et al.  Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial , 1999, The Lancet.

[21]  F. Sallusto,et al.  Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells , 2000, Nature Immunology.

[22]  C. Liu,et al.  Plasmacytoid Dendritic Cells Synergize with Myeloid Dendritic Cells in the Induction of Antigen-Specific Antitumor Immune Responses , 2007, The Journal of Immunology.

[23]  H. Rammensee,et al.  Identification of HLA-A2-restricted T-cell epitopes derived from the MUC1 tumor antigen for broadly applicable vaccine therapies. , 1999, Blood.

[24]  D. Czerwinski,et al.  Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. , 2002, Blood.

[25]  Peter Brossart,et al.  Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients. , 2006, Cancer research.

[26]  E. Gilboa,et al.  Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo , 1996, The Journal of experimental medicine.

[27]  J. Prieto,et al.  The Extra Domain A from Fibronectin Targets Antigens to TLR4-Expressing Cells and Induces Cytotoxic T Cell Responses In Vivo1 , 2007, The Journal of Immunology.

[28]  P. Brossart,et al.  Cellular Immunotherapy with Dendritic Cells in Cancer: Current Status , 2004, Stem cells.

[29]  W. Lehmacher,et al.  Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial , 2004, The Lancet.

[30]  T. Sauerbruch,et al.  Dendritic cells pulsed with alpha-galactosylceramide induce anti-tumor immunity against pancreatic cancer in vivo. , 2006, International immunology.

[31]  Edgar G. Engleman,et al.  Vaccination of patients with B–cell lymphoma using autologous antigen–pulsed dendritic cells , 1996, Nature Medicine.

[32]  A. Ballestrero,et al.  Dendritic cells transfected with tumor RNA for the induction of antitumor CTL in colorectal cancer , 2003, Cancer Gene Therapy.

[33]  L. Moretta,et al.  Early liaisons between cells of the innate immune system in inflamed peripheral tissues. , 2005, Trends in immunology.

[34]  L. Kanz,et al.  Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. , 2000 .

[35]  L. Kanz,et al.  Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells. , 2003, Blood.

[36]  R. Steinman,et al.  The use of dendritic cells in cancer immunotherapy. , 2003, Current opinion in immunology.

[37]  D. Tough,et al.  Preferential Induction of CD4+ T Cell Responses through In Vivo Targeting of Antigen to Dendritic Cell-Associated C-Type Lectin-1 , 2006, The Journal of Immunology.

[38]  E. Engleman,et al.  Dendritic Cell-Based Xenoantigen Vaccination for Prostate Cancer Immunotherapy1 , 2001, The Journal of Immunology.

[39]  P. Triozzi,et al.  Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer , 2000, Cancer.

[40]  C. Figdor,et al.  Targeting antigens to dendritic cells in vivo. , 2006, Immunobiology.

[41]  Steven A. Rosenberg,et al.  Progress in human tumour immunology and immunotherapy , 2001, Nature.

[42]  Hans-Georg Rammensee,et al.  The Tübingen approach: identification, selection, and validation of tumor-associated HLA peptides for cancer therapy , 2004, Cancer Immunology, Immunotherapy.

[43]  A. Anichini,et al.  Autologous dendritic cells derived from CD34+ progenitors and from monocytes are not functionally equivalent antigen-presenting cells in the induction of melan-A/Mart-1(27-35)-specific CTLs from peripheral blood lymphocytes of melanoma patients with low frequency of CTL precursors. , 1997, Cancer research.

[44]  E. Engleman,et al.  Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma--a feasibility study. , 1999, Blood.

[45]  R. Förster,et al.  Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells. , 2002, Blood.

[46]  Mark M. Davis,et al.  Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[47]  A. Mackensen,et al.  Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma. , 2006, Journal of Clinical Oncology.

[48]  T. Luft,et al.  Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli. , 2003, Blood.

[49]  C. Figdor,et al.  Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody. , 2005, Blood.

[50]  J. Banchereau,et al.  GM-CSF and TNF-α cooperate in the generation of dendritic Langerhans cells , 1992, Nature.

[51]  P. Brossart,et al.  Delivery of tumor-derived RNA for the induction of cytotoxic T-lymphocytes , 2003, Gene Therapy.

[52]  E. Gilboa,et al.  Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. , 2002, The Journal of clinical investigation.

[53]  E. Engleman,et al.  Dendritic cells in cancer immunotherapy. , 2000, Annual review of immunology.

[54]  S. Rosenberg,et al.  Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes , 2006, Science.

[55]  H. Rammensee,et al.  Induction of Adipophilin-Specific Cytotoxic T Lymphocytes Using a Novel HLA-A2-Binding Peptide That Mediates Tumor Cell Lysis , 2004, Cancer Research.

[56]  A. Thomson,et al.  Tolerogenic dendritic cells and the quest for transplant tolerance , 2007, Nature Reviews Immunology.

[57]  D. Baltimore,et al.  Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[58]  C Caux,et al.  Immunobiology of dendritic cells. , 2000, Annual review of immunology.

[59]  C. Maliszewski,et al.  In vivo generation of human dendritic cell subsets by Flt3 ligand , 2000 .

[60]  H. Nisenbaum,et al.  Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  H. Einsele,et al.  Idiotype vaccination of multiple myeloma patients using monocyte-derived dendritic cells. , 2003, Haematologica.

[62]  A. Bringmann,et al.  TLR ligands differentially affect uptake and presentation of cellular antigens. , 2007, Blood.

[63]  Chung-Pin Li,et al.  Combination of Conformal Radiotherapy and Intratumoral Injection of Adoptive Dendritic Cell Immunotherapy in Refractory Hepatoma , 2005, Journal of immunotherapy.

[64]  H. Rammensee,et al.  Her-2/neu-derived peptides are tumor-associated antigens expressed by human renal cell and colon carcinoma lines and are recognized by in vitro induced specific cytotoxic T lymphocytes. , 1998, Cancer research.

[65]  N. Shastri,et al.  In vivo targeting of dendritic cells for activation of cellular immunity using vaccine carriers based on pH-responsive microparticles. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[66]  Antonio Lanzavecchia,et al.  Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming , 2004, Nature Immunology.

[67]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[68]  Edgar G. Engleman,et al.  Dendritic Cells Injected Via Different Routes Induce Immunity in Cancer Patients1 , 2001, The Journal of Immunology.

[69]  V. Cerundolo,et al.  Dendritic Cell Function Can Be Modulated through Cooperative Actions of TLR Ligands and Invariant NKT Cells1 , 2007, The Journal of Immunology.

[70]  P. Brossart,et al.  Transfection of Dendritic Cells with RNA Induces CD4- and CD8-Mediated T Cell Immunity Against Breast Carcinomas and Reveals the Immunodominance of Presented T Cell Epitopes1 , 2003, The Journal of Immunology.