HLA-Identical Dendritic-Leukemic Cell Hybrids Generate Specific CTLs in Vitro

Abstract

hile being instrumental in the treatment of leukemic relapse after allogeneic hematopoietic stem cell transplantation, the impact of donor lymphocyte infusion (DLI) and its effectiveness remain debatable. Consequently it is widely accepted that more efforts are needed in order to make DLI more effective. This communication thus deals with the generation of specific CTLs in the clinical setting of HLA matched hematopoietic stem cell transplantation, to be used as an improved DLI treatment for post-transplantation relapsed leukemias. We assessed the potential of fused dendritic cells from donor origin, with leukemic cells from the HLA matched recipient for the generation of donor anti-tumor CTLs. Leukemic cells and donor dendritic cells were fused using polyethylene glycol (PEG). The hybrids were analyzed for double phenotype of both DC and tumor, and used for the education and generation of cytotoxic donor lymphocytes. Results demonstrate that efficient and specific CTLs can be generated and used in vitro for the elimination of the recipient tumor cells. These results form the basis for the establishment of a novel methodology aimed at generating active or passive anti-leukemic vaccine in relapsed patients.

Share and Cite:

R. Eshel, M. Shpringer, N. Voskobinik, A. Vexler, R. Ben-Yosef, I. Fabian, B. Tartakovsky and E. Naparstek, "HLA-Identical Dendritic-Leukemic Cell Hybrids Generate Specific CTLs in Vitro," Journal of Cancer Therapy, Vol. 1 No. 3, 2010, pp. 142-151. doi: 10.4236/jct.2010.13023.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] F. I. Alamdari, T. Rasmuson, K. Grankvist, et al., “Angiogenesis and Other Markers for Prediction of Survival in Metastatic Renal Cell Carcinoma,” Scandinavian Journal of Urology and Nephrology, Vol. 41, No. 1, 2007, pp. 5-9.
[2] L. Glouchkova, B. Ackermann and D. Dilloo, “Leukemia Vaccines,” Acta Haematologica, Vol. 110, No. 4, 2003, pp. 160-170.
[3] M. Robin, M. H. Schlageter, C. Chomienne, et al., “Targeted Immunotherapy in Acute Myeloblastic Leukemia: From Animals to Humans,” Cancer Immunology and Immunotherapy, Vol. 54, No. 10, 2005, pp. 933-943.
[4] I. M. Borrello and E. M. Sotomayor, “Cancer Vaccines for Hematologic Malignancies,” Cancer Control, Vol. 9, No. 2, 2002, pp. 138-151.
[5] J. Gong, D. Avigan, D. Chen, et al., “Activation of Antitumor Cytotoxic T Lymphocytes by Fusions of Human Dendritic Cells and Breast Carcinoma Cells,” Proceedings of National Academy Sciences, Vol. 97, No. 6, 2000(a), pp. 2715-2718.
[6] J. Gong, D. Chen, M. Kashiwaba, et al., “Induction of Antitumor Activity by Immunization with Fusions of Dendritic and Carcinoma Cells,” Nature Medicine, Vol. 3, No. 4, 1997, pp. 558-561.
[7] M. Klammer, M. Waterfall, K. Samuel, et al., “Fusion Hybrids of Dendritic Cells and Autologous Myeloid Blasts as a Potential Cellular Vaccine for Acute Myeloid Leukaemia,” British Journal of Haematology, Vol. 129, No. 3, 2005, pp. 340-349.
[8] R. Ridolfi, L. Ridolfi, M. Petrini, L. Fiammenghi and A. Riccobon, “Dendritic Cell Vaccination and Immunosti- mulation in Advanced Melanoma,” Expert Review of Vaccines, Vol. 2, No. 6, 2003, pp. 825-833.
[9] Y. Becker, “Immunological and Regulatory Functions of Uninfected and Virus Infected Immature and Mature Subtypes of Dendritic Cells - A Review,” Virus Genes, Vol. 26, No. 2, 2003, pp. 119-130.
[10] R. Stripecke, A. M. Levine, V. Pullarkat, et al., “Immunotherapy with Acute Leukemia Cells Modified into Antigen-Presenting Cells: Ex vivo Culture and Gene Transfer Methods,” Leukemia, Vol. 16, No. 10, 2002, pp. 1974- 1983.
[11] R. A. Willemsen, C. Ronteltap, P. Chames, et al., “T Cell Retargeting with MHC Class I-Restricted Antibodies: The CD28 Costimulatory Domain Enhances Antigen- Specific Cytotoxicity and Cytokine Production,” Journal of Immunology, Vol. 174, No. 12, 2005, pp. 7853-7858.
[12] E. Ranieri, M. Gigante, W. J. Storkus, et al., “Translational Mini-Review Series on Vaccines: Dendritic Cell- based Vaccines in Renal Cancer,” Clinical and Experimental Immunology, Vol. 147, No. 3, 2007, pp. 395-400.
[13] J. Galea-Lauri, D. Darling, G. Mufti, et al., “Eliciting Cytotoxic T Lymphocytes against Acute Myeloid Leukemia-Derived Antigens: Evaluation of Dendritic Cell- Leukemia Cell Hybrids and Other Antigen-Loading Strategies for Dendritic Cell-Based Vaccination,” Cancer Immunology and Immunotherapy, Vol. 51, 2002, pp. 299-310.
[14] W. Herr, E. Ranieri, W. Olson, et al., “Mature Dendritic Cells Pulsed with Freeze-Thaw Cell Lysates Define an Effective in Vitro Vaccine Designed to Elicit EBV-Specific CD4(+) and CD8(+) T Lymphocyte Responses,” Blood, Vol. 96, No. 5, 2000, pp. 1857-1864.
[15] J. J. Lee, C. E. Nam, J. H. Nam, et al., “Generation of Cytotoxic Donor CD8+ T Cells against Relapsing Leukemic Cells Following Allogeneic Transplantation by Stimulation with Leukemic Cell- or Leukemic Lysate Pulsed Donor Cell-Derived Dendritic Cells,” Leukemia Research, Vol. 28, No. 5, 2004, pp. 517-524.
[16] Y. Liu, W. Zhang, T. Chan, et al., “Engineered Fusion Hybrid Vaccine of IL-4 Gene-Modified Myeloma and Relative Mature Dendritic Cells Enhances Antitumor Immunity,” Leukemia Research, Vol. 26, No. 8, 2002, pp. 757-763.
[17] D. Montagna, R. Maccario, E. Montini, et al., “Generation and Ex vivo Expansion of Cytotoxic T Lymphocytes Directed toward Different Types of Leukemia or Myelodysplastic Cells Using both HLA-Matched and Partially Matched Donors,” Experimental Hematology, Vol. 31, No. 11, 2003, pp. 1031-1038.
[18] W. Song, H. L. Kong, H. Carpenter, et al., “Dendritic Cells Genetically Modified with an Adenovirus Vector Encoding the cDNA for a Model Antigen Induce Protective and Therapeutic Antitumor Immunity,” Journal of Experimental Medicine, Vol. 186, No. 8, 1997, pp. 1247- 1256.
[19] D. Avigan, “Dendritic Cells: Development, Function and Potential Use for Cancer Immunotherapy,” Blood Review, Vol. 13, No. 1, 1999, pp. 51-64.
[20] J. Gong, N. Nikrui, D. Chen, et al., “Fusions of Human Ovarian Carcinoma Cells with Autologous or Allogeneic Dendritic Cells Induce Antitumor Immunity,” Journal of Immunology, Vol. 165, No. 3, 2000(b), pp. 1705-1711.
[21] A. Nencioni and P. Brossart, “Cellular Immunotherapy with Dendritic Cells in Cancer: Current Status,” Stem Cells, Vol. 22, No. 4, 2004, pp. 501-513.
[22] S. W. Krause, C. Neumann, A. Soruri, et al., “The Treatment of Patients with Disseminated Malignant Melanoma by Vaccination with Autologous Cell Hybrids of Tumor Cells and Dendritic Cells,” Journal of Immunotherapy, Vol. 25, No. 5, 2002, pp. 421-428.
[23] D. K. Schui, L. Singh, B. Schneider, et al., “Inhibiting Effects on the Induction of Cytotoxic T Lymphocytes by Dendritic Cells Pulsed with Lysates from Acute Myeloid Leukemia Blasts,” Leukemia Research, Vol. 26, No. 4, 2002, pp. 383-389.
[24] L. M. Faber, S. A. van Luxemburg-Heijs, W. F. Veenhof, et al., “Generation of CD4+ Cytotoxic T-Lymphocyte Clones from a Patient with Severe Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation: Implications for Graft-Versus-Leukemia Reactivity,” Blood, Vol. 86, No. 7, 1995, pp. 2821-2828.
[25] H. J. Kolb, J. Mittermuller, C. Clemm, et al., “Donor Leukocyte Transfusions for Treatment of Recurrent Chronic Myelogenous Leukemia in Marrow Transplant Patients,” Blood, Vol. 76, No. 12, 1990, pp. 2462-2465.
[26] P. A. McSweeney, D. Niederwieser, J. A. Shizuru, et al., “Hematopoietic Cell Transplantation in Older Patients with Hematologic Malignancies: Replacing High-Dose Cytotoxic Therapy with Graft-Versus-Tumor Effects,” Blood, Vol. 97, No. 11, 2001, pp. 3390-3400.
[27] T. Mutis, R. Verdijk, E. Schrama, et al., “Feasibility of Immunotherapy of Relapsed Leukemia with Ex Vivo- Generated Cytotoxic T Lymphocytes Specific for Hematopoietic System-Restricted Minor Histocompatibility Antigens,” Blood, Vol. 93, No. 7, 1999, pp. 2336-2341.
[28] E. Naparstek, A. Nagler, R. Or, et al., “Allogeneic Cell- mediated Immunotherapy Using Donor Lymphocytes for Prevention of Relapse in Patients Treated with Allogeneic Bone Marrow Transplantation for Hematological Malignancies,” Clinical Transplantation, 1996, pp. 281-290.
[29] E. Naparstek, R. Or, A. Nagler, et al., “T-Cell-Depleted Allogeneic Bone Marrow Transplantation for Acute Leukaemia Using Campath-1 Antibodies and Post-Transplant Administration of Donor’s Peripheral Blood Lymphocytes for Prevention of Relapse,” British Journal of Haematology, Vol. 89, No. 3, 1995, pp. 506-515.
[30] S. Slavin, E. Naparstek, A. Nagler, et al., “Allogeneic Cell Therapy with Donor Peripheral Blood Cells and Recombinant Human Interleukin-2 to Treat Leukemia Relapse after Allogeneic Bone Marrow Transplantation,” Blood, Vol. 87, No. 6, 1996(a), pp. 2195-2204.
[31] S. Slavin, E. Naparstek, A. Nagler, et al., “Allogeneic Cell Therapy: The Treatment of Choice for All Hematologic Malignancies Relapsing Post BMT,” Blood, Vol. 87, No. 9, 1996(b), pp. 4011-4013.
[32] R. J. Soiffer, “Donor Lymphocyte Infusions for Acute Myeloid Leukaemia,” Best Practice & Research Clinical Haematology, Vol. 21, No. 3, 2008, pp. 455-466.
[33] M. Di Nicola, R. Zappasodi, C. Carlo-Stella, et al., “Vaccination with Autologous Tumor-Loaded Dendritic Cells Induces Clinical and Immunologic Responses in Indolent B-Cell Lymphoma Patients with Relapsed and Measurable Disease: A Pilot Study,” Blood, Vol. 113, No. 1, 2009, pp. 18-27.
[34] B. Vasir, V. Borges, Z. Wu, et al., “Fusion of Dendritic Cells with Multiple Myeloma Cells Results in Maturation and Enhanced Antigen Presentation,” British Journal of Haematology, Vol. 129, No. 5, 2005, pp. 687-700.
[35] J. O. Cullis, Y. Z. Jiang, A. P. Schwarer, et al., “Donor Leukocyte Infusions for Chronic Myeloid Leukemia in Relapse after Allogeneic Bone Marrow Transplantation,” Blood, Vol. 79, No. 5, 1992, pp. 1379-1381.
[36] W. R. Drobyski, C. A. Keever, M. S. Roth, et al., “Salvage Immunotherapy Using Donor Leukocyte Infusions as Treatment for Relapsed Chronic Myelogenous Leukemia after Allogeneic Bone Marrow Transplantation: Efficacy and Toxicity of a Defined T-Cell Dose,” Blood, Vol. 82, No. 8, 1993, pp. 2310-2318.
[37] D. L. Porter, M. S. Roth, S. J. Lee, et al., “Adoptive Immunotherapy with Donor Mononuclear Cell Infusions to Treat Relapse of Acute Leukemia or Myelodysplasia after Allogeneic Bone Marrow Transplantation,” Bone Marrow Transplant, Vol. 18, No. 16, 1996, pp. 975-980.
[38] R. Ivanov, A. Hagenbeek and S. Ebeling, “Towards Immunogene Therapy of Hematological Malignancies,” Experimental Hematology, Vol. 34, No. 3, 2006, pp. 251- 263.
[39] B. D. Johnson, E. E. Becker and R. L. Truitt, “Graft- vs.-Host and Graft-vs.-Leukemia Reactions after Delayed Infusions of Donor T-Subsets,” Biology of Blood and Marrow Transplantation, Vol. 5, No. 3, 1999, pp. 123-132.
[40] G. Xia, R. L. Truitt and B. D. Johnson, “Graft-versus- Leukemia and Graft-versus-Host Reactions after Donor Lymphocyte Infusion are Initiated by Host-Type Antigen-Presenting Cells and Regulated by Regulatory T Cells in Early and Long-Term Chimeras,” Biology of Blood and Marrow Transplantation, Vol. 12, No. 4, 2006, pp. 397- 407.
[41] E. P. Alyea, C. Canning, D. Neuberg, et al., “CD8+ Cell Depletion of Donor Lymphocyte Infusions Using CD8 Monoclonal Antibody-Coated High-Density Microparticles (CD8-HDM) after Allogeneic Hematopoietic Stem Cell Transplantation: A Pilot Study,” Bone Marrow Tran- splant, Vol. 34, No. 2, 2004, pp. 123-128.
[42] R. J. Soiffer, E. P. Alyea, E. Hochberg, et al., “Randomized Trial of CD8+ T-Cell Depletion in the Prevention of Graft-versus-Host Disease Associated with Donor Lymphocyte Infusion,” Biology of Blood and Marrow Transplantation, Vol. 8, No. 11, 2002, pp. 625-632.
[43] D. L. Porter, B. L. Levine, N. Bunin, et al., “A Phase 1 Trial of Donor Lymphocyte Infusions Expanded and Activated ex vivo via CD3/CD28 Costimulation,” Blood, Vol. 107, No. 4, 2006, pp. 1325-1331.
[44] C. Bonini, G. Ferrari, S. Verzeletti, et al., “HSV-TK Gene Transfer into Donor Lymphocytes for Control of Allogeneic Graft-versus-Leukemia,” Science, Vol. 276, No. 5391, 1997, pp. 1719-1724.
[45] K. C. Hsu, C. A. Keever-Taylor, A. Wilton, et al., “Improved Outcome in HLA-Identical Sibling Hematopoietic Stem-Cell Transplantation for Acute Myelogenous Leukemia Predicted by KIR and HLA Genotypes,” Blood, Vol. 105, No. 12, 2005, pp. 4878-4884.
[46] L. Ruggeri, M. Capanni, E. Urbani, et al., “Effectiveness of Donor Natural Killer Cell Alloreactivity in Mismatch- ed Hematopoietic Transplants,” Science, Vol. 295, No. 5562, 2002, pp. 2097-2100.
[47] B. Carlsson, W. S. Cheng, T. H. Totterman, et al., “Ex vivo Stimulation of Cytomegalovirus (CMV)-Specific T Cells Using CMV pp65-Modified Dendritic Cells as Stimulators,” British Journal of Haematology, Vol. 121, No. 3, 2003, pp. 428-438.
[48] S. El Marsafy and M. Bagot, A. Bensussan, et al., “Dendritic Cells in the Skin-Potential Use for Melanoma Treatment,” Pigment Cell and Melanoma Research, Vol. 22, No. 1, 2009, pp. 30-41.
[49] T. J. Lehrfeld, D. I. Lee, “Dendritic Cell Vaccines for the Treatment of Prostate Cancer,” Urology and Nephrology, Vol. 26, No. 1, 2008, pp. 576-580.
[50] J. H. Falkenburg, “Immunotherapy of Hematological Malignancies with Dendritic Cells,” Hematology Journal, Vol. 5, No. (Suppl. 3), 2004, pp. S96-S99.
[51] W. Guo, Y. Guo, S. Tang, et al., “Dendritic Cell-Ewing’s Sarcoma Cell Hybrids Enhance Antitumor Immunity,” Clinical Orthopaedics and Related Research, Vol. 466, No. 9, 2008, pp. 2176-2183.
[52] K. Imura, Y. Ueda, T. Hayashi, et al., “Induction of Cytotoxic T Lymphocytes against Human Cancer Cell Lines Using Dendritic Cell-Tumor Cell Hybrids Generated by a Newly Developed Electrofusion Technique,” International Journal of Oncology, Vol. 29, No. 3, 2006, pp. 531-539.
[53] R. Savai, R. T. Schermuly, S. S. Pullamsetti, et al., “A Combination Hybrid-Based Vaccination/Adoptive Cellular Therapy to Prevent Tumor Growth by Involvement of T Cells,” Cancer Research, Vol. 67, No. 11, 2007, pp. 5443-5453.
[54] T. Yasuda, T. Kamigaki, T. Nakamura, et al., “Dendritic Cell-Tumor Cell Hybrids Enhance the Induction of Cytotoxic T Lymphocytes against Murine Colon Cancer: A Comparative Analysis of Antigen Loading Methods for the Vaccination of Immunotherapeutic Dendritic Cells,” Oncology Reports, Vol. 16, No. 6, 2006, pp. 1317-1324.
[55] J. H. Falkenburg, A. R. Wafelman, P. Joosten, et al., “Complete Remission of Accelerated Phase Chronic Myeloid Leukemia by Treatment with Leukemia-Reac- tive Cytotoxic T Lymphocytes,” Blood, Vol. 94, No. 4, 1999, pp. 1201-1208.
[56] D. Avigan, B. Vasir, J. Gong, et al., “Fusion Cell Vaccination of Patients with Metastatic Breast and Renal Cancer Induces Immunological and Clinical Responses,” Clin Cancer Research, Vol. 10, No. 14, 2004, pp. 4699-4708.
[57] S. Shu, R. Zheng, W. T. Lee, et al., “Immunogenicity of Dendritic-Tumor Fusion Hybrids and their Utility in Cancer Immunotherapy,” Critical Reviews in Immunology, Vol. 27, No. 5, 2007, pp. 463-483.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.