Dendritic cells therapy
In the Gorter Model, the patient comes to the clinic for a blood draw (50 ml) at day 1. The laboratory processes the blood, monocytes are harvested and, in a six-day period, changed into dendritic cells.
Then, if tumor tissue is available, the dendritic cells are exposed to the specific cancer antigen of the patient.
Finally, these sensitized and programmed dendritic cells are re-infused into the patient on day 7. It is recommended that the patient undergoes an infusion (vaccination) with dendritic cells at least six times.
The dendritic cell (DC) was championed by Steinman and Chon in 1973, as a novel stellate cell, DC were identified in the spleen of mice.
Because of their shape under the microscope with all their tentacles, they were called dendritic cells (Greek: dendros = tree, branches). [32,15]
Not until the mid-80s of the last century, it was noticed that DC belong to the same family of cells, which had been discovered more than one hundred years ago by Langerhans.16
Later on, DC were also documented in other lymphatic organs and in non-lymphatic tissues. The Nobel Prize in Physiology and Medicine in 2011 was divided, with one half jointly to Bruce A. Beutler and Jules A. Hoffmann for their discoveries concerning the activation of innate immunity and the other half to Ralph M. Steinman for his discovery of the dendritic cell and its role in adaptive immunity.
The award of 2011 Nobel Prize for Physiology or Medicine demonstrates the significance of this cell type in health and disease.
Reuters profiled Rockefeller University's Ralph Steinman and his efforts to treat his own pancreatic cancer using his Nobel Prize-winning dendritic cell therapy. Although Steinman died right days before receiving the Nobel Prize, he lived more that three years longer than expected.
Ralph Steinman himself believed that it was the dendritic cell therapy that prolonged his life. Read more about the Nobel Prize winner and his dendritic cell therapy
In the past decade, much has been learned regarding the use of the dendritic cells and their role in the development of cancer vaccines. Contrary to what was originally thought, dendritic cells are not capable of inducing an immune response unless they undergo activation.
Current vaccine approaches may incorporate foreign carrier proteins, adjuvants, cytokines and genetically engineered viruses in an attempt to increase immunogenicity. [24]
Dendritic cells express high levels of major histocompatibilitiy complex class I and II antigens. In 1990, Freudenthal and Steinman showed, that DC also express high levels of the immunomodulatory proteins B7.1 (CD80), B7.2 (CD86), CD 40, and two adhesins, the intracellular adhesion molecule ICAM-1 (CD54) and the lymphocyte function- associate protein LFA.3 (CD58). DC can also produce -producing cells.[25]γIL-12, a potent cytokine, that activates interferon.
The initial group of trials involving DC for the treatment of cancer used cells obtained from peripheral blood but they had difficulties because DC constitute less than 5% but in 1990 Markowics et al26 found that GM-CSF not only promotes dendritic cell survival, but also induces dendritic cell differentiation to mobile, reversibly-adherent cells with long-branched projections, changing the survival for up to 6 weeks. [26]
Lately, in 1994, Mehta-Damani et al27 were able to use DC to generate antigen- specific CD8+ cytotoxic T lymphocites (CTLs) from naïve precursors in vitro and in 1995 Mehta-Damani et al28 described an in vitro system for generating antigen- specific CD4+ T cells. In 1996, Hsu et al29 reported on the first clinical trial of antigen-pulsed dendritic cells.
This trial was designed to evaluated the efficacy of tumor-specific idiotype (Id) protein-pulsed autologous dendritic cells in the treatment of B-cell lymphoma.
Because of the success of the study by Hsu et al, Timmerman et al used the same approach in a larger number of patients with non-Hodgkin´s B-cell lymphoma.
Three monthly infusions of antigen-pulsed dendritic cells were administrered intravenously to each patient, followed by a fourth vaccination 2 to 6 months later.
The study concluded that Id-pulsed dendritic cell vaccination can induce T-cell and humoral anti-Id responses and (complete) tumor regression.
Characteristics of dendritic cells
There are a number of challenges associated with the development and optimization of dendritic cell-based cancer vaccines. The current approach of isolating and pulsing dendritic cells is difficult and expensive.
Ultimately, targeting and activating dendritic cells should be performed in vivo instead of the current in vitro approach. To attract dendritic cells into an accessible location into which an antigen and a dendritic cell activator can be injected or introduced, the numbers of DC may need to be expanded. [24]
Another challenge is the determination of which clinical endpoints should be measured. Most of the focus in cancer immunology has been on CD8+ CTL responses.
However, recent evidence has indicated that CD4+ T cells may be an equally critical component of the antitumor immune response. [38]
In practically all tissues in the body, DC form a close network of watch-dog cells, which identify and incorporate extracellular antigens through phagocytosis and endocytosis and thus, analyze their surroundings. Incorporated proteins (antigens) are then split into smaller peptides, linked to MHC-molecules and then transported to the surface (cell membrane) of the DC.
In this way, antigen peptides are made visible for T-Lymphocytes and cytotoxic cells. DC migrate actively from peripheral tissue to regional lymph nodes, where they communicate with resting T-Lymphocytes, and transmit their information.
Activation and maturation of dendritic cells
A well-functioning surveillance system recognizes damaging processes fast and with great detail, and to augment a quick and effective response.
For this purpose, DC carry on their surface receptors for millions of possible danger signals, which can be activated by micro-organisms, damaged- or cancerous cells, and interleukins and cytokines, which are produced by the body’s own tissues and T-Lymphocytes.
Induction of an immune response
In lymph nodes, DC interact with various lymphocyte sub-populations. Especially naïve T-lymphocytes communicate with DC by active searching over the surface of DC. Naïve T-lymphocytes are activated when they recognize an antigen, presented by the DC. Both CD4+ lymphocytes and CD8+ lymphocytes are activated in this way by DC and this process is called priming.
DC develop their full capacity for activating CD4+- and CD8+ lymphocytes after they have gone through their own maturation process, on their way from location of their activation by, for instance a cancerous cell, to the regional lymph nodes.
Today, it is still not certain how many activated and matured DC are necessary to induce a significant immune response against, for instance, a malignancy.
In animal models and in clinical studies, 100,000 to (rarely) 100,000,000 DC per vaccination have been used. In the Gorter Model, 5,000,000 to 15,000,000 DC per vaccination are commonly used.
Numbers of DC might vary secondary to the number and the fitness of monocytes, harvested from 100ml of peripheral blood of a patient.
In the Gorter Model, DC are manufactured from the patients own monocytes (“autologous, monocyte-derived dendritic cells”), and applied intacutaneously, intra- nodually, intra-tumorally, intra-thecally or intravenously, depending on location, kind of tumor, and other factors.
In addition, through leucopharese, many more monocytes can be harvested so that more dendritic cells for a vaccination can be manufactured.
References:
3.Caux C et al: GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells.
Nature (1992) 360: 258-261
4.Santiago-Schwarz F et al: TNF in combination with GM-CSF enhances the differentiation of neonatal cord blood stem cells into dendritic cells and macrophages.J Leukoc Biol (1992) 52: 274-
281
5.Herbst B et al: In vitro differentiation of CD34+ hematopoietic progenitor cells toward distinct dendritic cell subsets of the birbeck granule and MIIC- positive Langerhans cell and the interdigitating dendritic cell type.Blood (1996) 88: 2541-2548
6.Sallusto F, Lanzavecchia A: 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.J Exp Med. (1994) 179: 1109-1118
7.Peters J et al: Dendritic cells: From ontogenetic orphans to myelo-monocytic descendants.
Immunol Today (1996) 17:273-278
8.Mayordomo J et al: Bone Marrow-Derived Dendritic Cells Serve as Potent Adjuvants for Peptide- Based Antitumor Vaccines.Stem cells (1997) 15: 94-103
9.Hsu FJ et al: Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med (1996) 2: 52-58
10.Dietz AB, Litzow MR, Gastineau DA, Vuk-Pavlovic S: Engineering dendritic cell grafts for clinical trials in cellular immunotherapy of cancer: example of chronic myelogenous leukaemia. Croat Med J (2001) 42(4): 427-434
11.Sangro B, Qian C, Schmitz V, Prieto J: Gene therapy of hepatocellular carcinoma and gastrointestinal tumors. Ann NY Acad Sci (2002); 963: 6-12. 12.Qiu S, Ye S, Tang Z, Qian S, Li L: Feasibility of using hepatitis B virus surface antigen as target antigen in immunogeng therapy against cancer. Zhonghua Yi Xue Za Zhi (2002) 82: 253-256.
13.Liu B, Ye S, He P, Zheng N, Zhao, Sun R, Tang Z: Study of the cytotoxicity against human hepatocellular carcinoma cells induced by the MAGE-1 gene modified dendritic cells. Zhonghua Gan Zang Bing Za Zhi (2001) 9: 151-153.
14.Liu B, Ye S, He P, Xue Q, Gao D, Tang Z: Antitumor activities in vivo of interleukin-12 gene modified dendritic cells in murine models. Zhonghua Gan Zang Bing Za Zhi (2000) 8: 350-351.
15.Pedersen IM, Kitada S, Leoni LM, Zapata JM, Karras JG, Tsukada N, Kipps TJ, Choi YS, Bennetti F, Reed JC: Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1. Blood (2002) Sep 1;100(5):1795-1801.
16.Ruffini PA, Kwak LW: Immunotherapy of multiple myeloma. Semin Hematol (2001) 38:260-267.
17.Gong J, Koido S, Chen A, Tanaka Y, Huang L, Avigan D, Anderson K, Ohno T, Kufe D: Immunization against murine multiple myeloma with infusions of dendritic and plasmacytoma cells is potentiated by interleukin-12. Blood (2002) 99:2512-2517.
18.Liu Y, Zhang W, Chan T, Saxena A, Xiang J: Engineered fusion hybrid vaccine of IL-4 gene- modified myeloma and relative mature dendritic cells enhances antitumor immunity. Lek Res (2002)
26:757-763.
19.Zeis M, Frenzke H, Schmitz N, Uharek L, Steinmann J: Idiotype protein-pulsed dendritic cells produce strong ant-myeloma effects after syngeneic stem cell transplantation in mice. Bone Mattow Transplant (2002) 29:213-221.
20.Cull GM, Timms JM, Haynes AP, Russell NH, Irving WL, Ball JK: Dendritic cells cultured from mononuclear cells and CD34 cells in myeloma do not harbour human herpes virus 8. Br J Haematol (1998) 100:793-796.
21.Valone FH, Small E, MacKenzie M, Burch P, Lacy M, Peshwa MV, Laus R: Dendritic cell-based treatment of cancer: closing in on a cellular therapy. (in print).
22.Tanaka F, Yamaguchi H, Ohta M, Mashino K, Sonoda H, Sadanaga N, Inoue H, Mori M: Intratumoral injection of dendritic cells after treatment of anticancer drugs induces tumor-specific antitumor effect in vivo. Int J Cancer (2002) Sep 20; 101(3):265-269.
23.Stift A, Friedl J, Dubsky P, Bachleitner-Hofmann T, Benkoe T, Brostjan C, Jakesz R, Gnant M.: In vivo induction of dendritic cell-mediated cytotoxicity against allogeneic pancreatic carcinoma cells. Int J Oncol. 2003 Mar; 22(3):651-6.
24. Engleman E.G: Dendritic cell-Based cancer immunotherapie. Semin Oncol (2003) 30 (Suppl 8):23-
25.Freudenthal PS Engleman EG: The distinct surface of human blood dendritic cells, as observed after an improved isolation method. Proc Natl Acad Sci U S A 87: 7698-7702, 1990.
26.Markowicz S, Englenman EG: Granulocyte-macrophage colony-stimulating factor promotes differentiation and survival of human peripheral blood dendritic cells in vitro. J Clin Invest 85: 9555-
961, 1990.
27.Mehta-Damani A, Markowicz S, Englenman EG: Generation of antigen-specific CD8+ CTLs from naïve precursors. J immunol 153:996-1003, 1994.
28.Mehta-Damani A, Markowicz S, Englenman EG: Generation of antigen-specific CD4+ T cell lines from naïve precursors. J immunol 25: 1206-1211, 1995.
29.Hsu FJ, Benike C, Fagnone F, et al: Vaccination of patients with B cell lymphoma using autolugus antigen-pulsed dendritic cells. Nature Med 2:52-58, 1996.
30.Timmerman JM, Czerwinski DK, Davis TA, et al: Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: Clinical and immune responses in 35 patients. Blood 99:1517-1526, 2002
31.Liso A, Stocherl-Goldstein KE, Auffermann-Gretzinger S, et al: Idiotype vaccination using dendritic cells after autolugus peripheral blood progenitor cell trasplnatation for multiple myeloma. Biol Blood Marrow transplant 6:621-627, 2000.
32.Fecci PE, Mitchell DA, Archer GE, Morse MA, Lyerly HK, et al: The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors. Journal of Neuro- Oncology 64: 161-176, 2003.
33.Patrone F, Valbonesi M, Ballestrero Alberto: Autologous peripheral blood stem cells (PBSC) in breast cancer. Transfunsion and apheresis science 27 (2002) 167-173.
34.Office for national statistics, Morality, statistics, cause No 21, DH2 series, HMSO, 1996.
35.Wojas K, Tabarkiewicz J, Jankiewicz M, Rolinski J: Dendritic cells in peripheral blood of patients with breast and lung cancer a pilot study. Folia Histochem Cytobiol. 2004; 42(1): 45-8.
36.Pockaj BA, Basu GD, Pathangey LB, Gray RJ, Hernandez JL, Gendler SJ, Mukherjee P.Reduced
T-cell and dendritic cell function is related to cyclooxygenase-2 overexpression and prostaglandin E2 secretion in patients with breast cancer. Ann Surg Oncol. 2004 Mar;11(3):328-39.
37.Manna PP, Jaramillo A, Majumder K, Campbell LG, Fleming TP, Dietz JR, Dipersio JF, Mohanakumar T: Generation of CD8+ cytotoxic T lymphocytes against breast cancer cells by stimulation with mammaglobin-A-pulsed dendritic cells. Breast Cancer Res Treat. 2003 May;79(1):133-6.
38.Paradoll DM. Topalian SL: The role of CD4+ T cell responses in antitumor immunity. Curr Opin
Immunol 10: 588-594, 1998.
39.Bigotti G, Coli A, Castagnola D: Distribution of Langerhans cells and HLA class II molecules in prostatic carcinomas of different histopathological grade. Prostate. 1991;19(1):73-87.
40.Tjoa B, Boynton A, Kenny G, Ragde H, Misrock SL, Murphy G. Presentation of prostate tumor antigens by dendritic cells stimulates T-cell proliferation and cytotoxicity. Prostate. 1996
Jan;28(1):65-9.
41.Murphy G, Tjoa B, Ragde H, Kenny G, Boynton A.Phase I clinical trial: T-cell therapy for prostate cancer using autologous dendritic cells pulsed with HLA-A0201-specific peptides from prostate- specific membrane antigen. Prostate. 1996 Dec;29(6):371-80. 42.Tjoa BA, Erickson SJ, Bowes VA, Ragde H, Kenny GM, Cobb OE, Ireton RC, Troychak MJ, Boynton AL, Murphy GP: Follow-up evaluation of prostate cancer patients infused with autologous dendritic cells pulsed with PSMA peptides. Prostate. 1997 Sep 1;32(4):272-8. 43. Slovin SF, Kelly WK, Scher HI: Immunological approaches for the treatment of prostate cancer.
Semin Urol Oncol. 1998 Feb; 16(1):53-9. Review
44.Salgaller ML, Lodge PA, McLean JG, Tjoa BA, Loftus DJ, Ragde H, Kenny GM, Rogers M, Boynton AL, Murphy GP.: Report of immune Monitoring of prostate cancer patients undergoing T- Cell therapy using dendritics cells pulsed with HLA-A2-Specific peptides from prostate-specific membrane antigen (PSMA). The Prostate 35:144-151 (1998). 45.Salgaller ML, Tjoa BA, Lodge PA, Ragde H, Kenny G, Boynton A, Murphy GP.Dendritic cell-based immunotherapy of prostate cancer. Crit Rev Immunol. 1998;18(1-2):109-19.
46.Tjoa BA, Simmons SJ, Bowes VA, Ragde H, Rogers M, Elgamal A, Kenny GM, Cobb OE, Ireton RC, Troychak MJ, Salgaller ML, Boynton AL, Murphy GP: Evaluation of phase I/II clinical trials in prostate cancer with dendritic cells and PSMA peptides. Prostate. 1998 Jun 15;36(1):39-44.
47.Peshwa MV, Shi JD, Ruegg C, Laus R, van Schooten WC.Induction of prostate tumor-specific CD8+ cytotoxic T-lymphocytes in vitro using antigen-presenting cells pulsed with prostatic acid phosphatase peptide. Prostate. 1998 Jul 1;36(2):129-38.
48.Simmons SJ, Tjoa BA, Rogers M, Elgamal A, Kenny GM, Ragde H, Troychak MJ, Boynton AL, Murphy GP: GM-CSF as a systemic adjuvant in a phase II prostate cancer vaccine trial. Prostate.
1999 Jun 1;39(4):291-7.
49.Tjoa BA, Simmons SJ, Elgamal A, Rogers M, Ragde H, Kenny GM, Troychak MJ, Boynton AL, Murphy GP: Follow-up evaluation of a phase II prostate cancer vaccinetrial.Prostate. 1999 Jul
1;40(2):125-9.
50.Murphy GP, Snow P, Simmons SJ, Tjoa BA, Rogers MK, Brandt J, Healy CG, Bolton WE, Rodbold D: Use of artificial neural networks in evaluating prognostic factors determining the response to dendritic cells pulsed with PSMA peptides in prostate cancer patients.Prostate. 2000 Jan;42(1):67-
51.McNeel DG, Disis ML: Tumor vaccines for the management of prostate cancer. Arch Immunol Ther
Exp (Warsz). 2000;48(2):85-93. Review.
52.Heiser A, Dahm P, Yancey DR, Maurice MA, Boczkowski D, Nair SK, Gilboa E, Vieweg J. Human dendritic cells transfected with RNA encoding prostate-specific antigen stimulate prostate-specific CTL responses in vitro. J Immunol. 2000 May 15;164(10):5508-14.
53.Meidenbauer N, Harris DT, Spitler LE, Whiteside TL. Generation of PSA-reactive effector cells after vaccination with a PSA-based vaccine in patients with prostate cancer.Prostate. 2000 May
1;43(2):88-100.
In the Gorter Model, the patient comes to the clinic for a blood draw (50 ml) at day 1. The laboratory processes the blood, monocytes are harvested and, in a six-day period, changed into dendritic cells.
Then, if tumor tissue is available, the dendritic cells are exposed to the specific cancer antigen of the patient.
Finally, these sensitized and programmed dendritic cells are re-infused into the patient on day 7. It is recommended that the patient undergoes an infusion (vaccination) with dendritic cells at least six times.
The dendritic cell (DC) was championed by Steinman and Chon in 1973, as a novel stellate cell, DC were identified in the spleen of mice.
Because of their shape under the microscope with all their tentacles, they were called dendritic cells (Greek: dendros = tree, branches). [32,15]
Not until the mid-80s of the last century, it was noticed that DC belong to the same family of cells, which had been discovered more than one hundred years ago by Langerhans.16
Later on, DC were also documented in other lymphatic organs and in non-lymphatic tissues. The Nobel Prize in Physiology and Medicine in 2011 was divided, with one half jointly to Bruce A. Beutler and Jules A. Hoffmann for their discoveries concerning the activation of innate immunity and the other half to Ralph M. Steinman for his discovery of the dendritic cell and its role in adaptive immunity.
The award of 2011 Nobel Prize for Physiology or Medicine demonstrates the significance of this cell type in health and disease.
Reuters profiled Rockefeller University's Ralph Steinman and his efforts to treat his own pancreatic cancer using his Nobel Prize-winning dendritic cell therapy. Although Steinman died right days before receiving the Nobel Prize, he lived more that three years longer than expected.
Ralph Steinman himself believed that it was the dendritic cell therapy that prolonged his life. Read more about the Nobel Prize winner and his dendritic cell therapy
In the past decade, much has been learned regarding the use of the dendritic cells and their role in the development of cancer vaccines. Contrary to what was originally thought, dendritic cells are not capable of inducing an immune response unless they undergo activation.
Current vaccine approaches may incorporate foreign carrier proteins, adjuvants, cytokines and genetically engineered viruses in an attempt to increase immunogenicity. [24]
Dendritic cells express high levels of major histocompatibilitiy complex class I and II antigens. In 1990, Freudenthal and Steinman showed, that DC also express high levels of the immunomodulatory proteins B7.1 (CD80), B7.2 (CD86), CD 40, and two adhesins, the intracellular adhesion molecule ICAM-1 (CD54) and the lymphocyte function- associate protein LFA.3 (CD58). DC can also produce -producing cells.[25]γIL-12, a potent cytokine, that activates interferon.
The initial group of trials involving DC for the treatment of cancer used cells obtained from peripheral blood but they had difficulties because DC constitute less than 5% but in 1990 Markowics et al26 found that GM-CSF not only promotes dendritic cell survival, but also induces dendritic cell differentiation to mobile, reversibly-adherent cells with long-branched projections, changing the survival for up to 6 weeks. [26]
Lately, in 1994, Mehta-Damani et al27 were able to use DC to generate antigen- specific CD8+ cytotoxic T lymphocites (CTLs) from naïve precursors in vitro and in 1995 Mehta-Damani et al28 described an in vitro system for generating antigen- specific CD4+ T cells. In 1996, Hsu et al29 reported on the first clinical trial of antigen-pulsed dendritic cells.
This trial was designed to evaluated the efficacy of tumor-specific idiotype (Id) protein-pulsed autologous dendritic cells in the treatment of B-cell lymphoma.
Because of the success of the study by Hsu et al, Timmerman et al used the same approach in a larger number of patients with non-Hodgkin´s B-cell lymphoma.
Three monthly infusions of antigen-pulsed dendritic cells were administrered intravenously to each patient, followed by a fourth vaccination 2 to 6 months later.
The study concluded that Id-pulsed dendritic cell vaccination can induce T-cell and humoral anti-Id responses and (complete) tumor regression.
Characteristics of dendritic cells
There are a number of challenges associated with the development and optimization of dendritic cell-based cancer vaccines. The current approach of isolating and pulsing dendritic cells is difficult and expensive.
Ultimately, targeting and activating dendritic cells should be performed in vivo instead of the current in vitro approach. To attract dendritic cells into an accessible location into which an antigen and a dendritic cell activator can be injected or introduced, the numbers of DC may need to be expanded. [24]
Another challenge is the determination of which clinical endpoints should be measured. Most of the focus in cancer immunology has been on CD8+ CTL responses.
However, recent evidence has indicated that CD4+ T cells may be an equally critical component of the antitumor immune response. [38]
In practically all tissues in the body, DC form a close network of watch-dog cells, which identify and incorporate extracellular antigens through phagocytosis and endocytosis and thus, analyze their surroundings. Incorporated proteins (antigens) are then split into smaller peptides, linked to MHC-molecules and then transported to the surface (cell membrane) of the DC.
In this way, antigen peptides are made visible for T-Lymphocytes and cytotoxic cells. DC migrate actively from peripheral tissue to regional lymph nodes, where they communicate with resting T-Lymphocytes, and transmit their information.
Activation and maturation of dendritic cells
A well-functioning surveillance system recognizes damaging processes fast and with great detail, and to augment a quick and effective response.
For this purpose, DC carry on their surface receptors for millions of possible danger signals, which can be activated by micro-organisms, damaged- or cancerous cells, and interleukins and cytokines, which are produced by the body’s own tissues and T-Lymphocytes.
Induction of an immune response
In lymph nodes, DC interact with various lymphocyte sub-populations. Especially naïve T-lymphocytes communicate with DC by active searching over the surface of DC. Naïve T-lymphocytes are activated when they recognize an antigen, presented by the DC. Both CD4+ lymphocytes and CD8+ lymphocytes are activated in this way by DC and this process is called priming.
DC develop their full capacity for activating CD4+- and CD8+ lymphocytes after they have gone through their own maturation process, on their way from location of their activation by, for instance a cancerous cell, to the regional lymph nodes.
Today, it is still not certain how many activated and matured DC are necessary to induce a significant immune response against, for instance, a malignancy.
In animal models and in clinical studies, 100,000 to (rarely) 100,000,000 DC per vaccination have been used. In the Gorter Model, 5,000,000 to 15,000,000 DC per vaccination are commonly used.
Numbers of DC might vary secondary to the number and the fitness of monocytes, harvested from 100ml of peripheral blood of a patient.
In the Gorter Model, DC are manufactured from the patients own monocytes (“autologous, monocyte-derived dendritic cells”), and applied intacutaneously, intra- nodually, intra-tumorally, intra-thecally or intravenously, depending on location, kind of tumor, and other factors.
In addition, through leucopharese, many more monocytes can be harvested so that more dendritic cells for a vaccination can be manufactured.
References:
3.Caux C et al: GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells.
Nature (1992) 360: 258-261
4.Santiago-Schwarz F et al: TNF in combination with GM-CSF enhances the differentiation of neonatal cord blood stem cells into dendritic cells and macrophages.J Leukoc Biol (1992) 52: 274-
281
5.Herbst B et al: In vitro differentiation of CD34+ hematopoietic progenitor cells toward distinct dendritic cell subsets of the birbeck granule and MIIC- positive Langerhans cell and the interdigitating dendritic cell type.Blood (1996) 88: 2541-2548
6.Sallusto F, Lanzavecchia A: 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.J Exp Med. (1994) 179: 1109-1118
7.Peters J et al: Dendritic cells: From ontogenetic orphans to myelo-monocytic descendants.
Immunol Today (1996) 17:273-278
8.Mayordomo J et al: Bone Marrow-Derived Dendritic Cells Serve as Potent Adjuvants for Peptide- Based Antitumor Vaccines.Stem cells (1997) 15: 94-103
9.Hsu FJ et al: Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med (1996) 2: 52-58
10.Dietz AB, Litzow MR, Gastineau DA, Vuk-Pavlovic S: Engineering dendritic cell grafts for clinical trials in cellular immunotherapy of cancer: example of chronic myelogenous leukaemia. Croat Med J (2001) 42(4): 427-434
11.Sangro B, Qian C, Schmitz V, Prieto J: Gene therapy of hepatocellular carcinoma and gastrointestinal tumors. Ann NY Acad Sci (2002); 963: 6-12. 12.Qiu S, Ye S, Tang Z, Qian S, Li L: Feasibility of using hepatitis B virus surface antigen as target antigen in immunogeng therapy against cancer. Zhonghua Yi Xue Za Zhi (2002) 82: 253-256.
13.Liu B, Ye S, He P, Zheng N, Zhao, Sun R, Tang Z: Study of the cytotoxicity against human hepatocellular carcinoma cells induced by the MAGE-1 gene modified dendritic cells. Zhonghua Gan Zang Bing Za Zhi (2001) 9: 151-153.
14.Liu B, Ye S, He P, Xue Q, Gao D, Tang Z: Antitumor activities in vivo of interleukin-12 gene modified dendritic cells in murine models. Zhonghua Gan Zang Bing Za Zhi (2000) 8: 350-351.
15.Pedersen IM, Kitada S, Leoni LM, Zapata JM, Karras JG, Tsukada N, Kipps TJ, Choi YS, Bennetti F, Reed JC: Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1. Blood (2002) Sep 1;100(5):1795-1801.
16.Ruffini PA, Kwak LW: Immunotherapy of multiple myeloma. Semin Hematol (2001) 38:260-267.
17.Gong J, Koido S, Chen A, Tanaka Y, Huang L, Avigan D, Anderson K, Ohno T, Kufe D: Immunization against murine multiple myeloma with infusions of dendritic and plasmacytoma cells is potentiated by interleukin-12. Blood (2002) 99:2512-2517.
18.Liu Y, Zhang W, Chan T, Saxena A, Xiang J: Engineered fusion hybrid vaccine of IL-4 gene- modified myeloma and relative mature dendritic cells enhances antitumor immunity. Lek Res (2002)
26:757-763.
19.Zeis M, Frenzke H, Schmitz N, Uharek L, Steinmann J: Idiotype protein-pulsed dendritic cells produce strong ant-myeloma effects after syngeneic stem cell transplantation in mice. Bone Mattow Transplant (2002) 29:213-221.
20.Cull GM, Timms JM, Haynes AP, Russell NH, Irving WL, Ball JK: Dendritic cells cultured from mononuclear cells and CD34 cells in myeloma do not harbour human herpes virus 8. Br J Haematol (1998) 100:793-796.
21.Valone FH, Small E, MacKenzie M, Burch P, Lacy M, Peshwa MV, Laus R: Dendritic cell-based treatment of cancer: closing in on a cellular therapy. (in print).
22.Tanaka F, Yamaguchi H, Ohta M, Mashino K, Sonoda H, Sadanaga N, Inoue H, Mori M: Intratumoral injection of dendritic cells after treatment of anticancer drugs induces tumor-specific antitumor effect in vivo. Int J Cancer (2002) Sep 20; 101(3):265-269.
23.Stift A, Friedl J, Dubsky P, Bachleitner-Hofmann T, Benkoe T, Brostjan C, Jakesz R, Gnant M.: In vivo induction of dendritic cell-mediated cytotoxicity against allogeneic pancreatic carcinoma cells. Int J Oncol. 2003 Mar; 22(3):651-6.
24. Engleman E.G: Dendritic cell-Based cancer immunotherapie. Semin Oncol (2003) 30 (Suppl 8):23-
25.Freudenthal PS Engleman EG: The distinct surface of human blood dendritic cells, as observed after an improved isolation method. Proc Natl Acad Sci U S A 87: 7698-7702, 1990.
26.Markowicz S, Englenman EG: Granulocyte-macrophage colony-stimulating factor promotes differentiation and survival of human peripheral blood dendritic cells in vitro. J Clin Invest 85: 9555-
961, 1990.
27.Mehta-Damani A, Markowicz S, Englenman EG: Generation of antigen-specific CD8+ CTLs from naïve precursors. J immunol 153:996-1003, 1994.
28.Mehta-Damani A, Markowicz S, Englenman EG: Generation of antigen-specific CD4+ T cell lines from naïve precursors. J immunol 25: 1206-1211, 1995.
29.Hsu FJ, Benike C, Fagnone F, et al: Vaccination of patients with B cell lymphoma using autolugus antigen-pulsed dendritic cells. Nature Med 2:52-58, 1996.
30.Timmerman JM, Czerwinski DK, Davis TA, et al: Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: Clinical and immune responses in 35 patients. Blood 99:1517-1526, 2002
31.Liso A, Stocherl-Goldstein KE, Auffermann-Gretzinger S, et al: Idiotype vaccination using dendritic cells after autolugus peripheral blood progenitor cell trasplnatation for multiple myeloma. Biol Blood Marrow transplant 6:621-627, 2000.
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