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Rejection of Experimental Hodgkins Lymphoma by T-Cells Engineered with a CD19 Chimeric Antigen Receptor

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DOI: 10.4236/jct.2012.35071    3,151 Downloads   4,814 Views  

ABSTRACT

T cells engineered to express chimeric antigen receptors (CARs) combining an external antibody binding domain with the CD3ζ T cell receptor (TCR) signaling domain for triggering cell activation are being used for immunotherapeutic targeting of tumor cells in a non-HLA restricted manner. In this study we transduced T cells with a CD19-CAR construct containing a truncated CD34 gene (tCD34) marker and used these to target the B cell antigen CD19 on the surface of a Hodgkin’s lymphoma (HL) cell line (L591) both in vitro and in vivo. Levels of tCD34 expression in transduced peripheral blood mononuclear cells (PBMCs) ranged from 6% - 20% and this was increased to 82% after selection for transduced tCD34+ cells. In vitro cytotoxicity testing on a CD19+ HL cell line (L591) showed specific cell lysis initiated by the CD19-CAR transduced PBMCs. Importantly, CD19-CAR T cells prevented the growth of L591 HL tumor cells when co-injected subcutaneously (sc) in 6/6 severe combined immunodeficient (SCID) mice. There was no evidence of anti-tumor activity when CD19-CAR T cells were infused intravenously (iv) at the same time as L591 HL tumor cells were injected sc. However, 3/6 SCID mice showed tumor rejection within 83 days after iv infusion of CD19-CAR T cells 3 - 9 days after establishment of L591 HL tumors, while all control animals succumbed to tumors within 60 days. Interestingly, immuno-histochemical analysis of L591 HL tumors demonstrated that CD19-CAR T cells were detected not earlier than 11 days after infusion within the tumor mass. These results suggest that CD19 is a potentially attractive target for the immunotherapy of HL.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

A. Swanson, E. Cheadle, D. Gilham, D. Crawford, S. Talbot and I. Johannessen, "Rejection of Experimental Hodgkins Lymphoma by T-Cells Engineered with a CD19 Chimeric Antigen Receptor," Journal of Cancer Therapy, Vol. 3 No. 5, 2012, pp. 553-561. doi: 10.4236/jct.2012.35071.

References

[1] A. B. Rickinson and E. Kieff, “Epstein-Barr Virus,” In: D. Knipe and P. Howley, Eds., Fields Virology, Lippincott Williams and Wilkins, Philadelphia, Vol. 2. 2007, pp. 2655-2700.
[2] C. M. Bollard, C. M. Rooney and H. E. Heslop, “T-Cell Therapy in the Treatment of Post-Transplant Lymphoproliferative Disease,” Nature Reviews Clinical Oncology, 2012 (in press).
[3] T. Haque, G. M. Wilkie, M. M. Jones, C. D. Higgins, G. Urquhart, P. Wingate, D. Burns, K. McAulay, M. Turner, C. Bellamy, P. L. Amlot, D. Kelly, A. Macgilchrist, M. K. Gandhi, A. J. Swerdlow and D. H. Crawford, “Allogeneic Cytotoxic T Cell Therapy for EBV-Positive Post Transplant Lymphoproliferative Disease: Results of a Phase II Multicentre Clinical Trial,” Blood, Vol. 110, No. 4, 2007, pp. 1123-1131. doi:10.1182/blood-2006-12-063008
[4] C. M. Rooney, C. A. Smith, C. Y. Ng, S. Loftin, C. Li, R. A. Krance, M. K. Brenner and H. E. Heslop, “Use of Gene-Modified Virus-Specific T Lymphocytes to Control Epstein-Barr-Virus-Related Lymphoproliferation,” Lan- cet, Vol. 345, No. 8941, 1995, pp. 9-13. doi:10.1016/S0140-6736(95)91150-2
[5] C. M. Bollard, L. Aguilar, K. C. Straathof, B. Gahn, M. H. Huls, A. Rousseau, J. Sixbey, M. V. Gresik, G. Carrum, M. Hudson, D. Dilloo, A. Gee, M. K. Brenner, C. M. Rooney and H. E. Heslop, “Cytotoxic T Lymphocyte Therapy for Epstein-Barr Virus+ Hodgkin’s Disease,” Journal of Experimental Medicine, Vol. 200, No. 12, 2004, pp. 1623-1633. doi:10.1084/jem.20040890
[6] S. Poppema, “Immunobiology and Pathophysiology of Hodgkin Lymphomas,” Hematology American Society of Hematology Education Program Book, Vol. 2005, No. 1, 2005, pp. 231-238. doi:10.1182/asheducation-2005.1.231
[7] A. van den Berg, L. Visser and S. Poppema, “High Expression of the CC Chemokine TARC in Reed-Sternberg Cells. A Possible Explanation for the Characteristic T-Cell Infiltratein Hodgkin’s Lymphoma,” The American Journal of Pathology, Vol. 154, No. 6, 1999, pp. 1685- 1691. doi:10.1016/S0002-9440(10)65424-7
[8] H. Herbst, H. D. Foss, J. Samol, I. Araujo, H. Klotzbach, H. Krause, A. Agathanggelou, G. Niedobitek and H. Stein, “Frequent Expression of Interleukin-10 by Epstein-Barr Virus-Harboring Tumor Cells of Hodgkin’s Disease,” Blood, Vol. 87, No. 7, 1996, pp. 2918-2829.
[9] Z. Eshhar, T. Waks, G. Gross and D. G. Schindler, “Spe- cific Activation and Targeting of Cytotoxic Lymphocytes through Chimeric Single Chains Consisting of Antibody-Binding Domains and the Gamma or Zeta Subunits of the Immunoglobulin and T-Cell Receptors,” Proceedings of the National Academy of Sciences, Vol. 90, No. 2, 1993, pp. 720-724. doi:10.1073/pnas.90.2.720
[10] Z. Eshhar, T. Waks, A. Bendavid and D. G. Schindler, “Functional Expression of Chimeric Receptor Genes in Human T Cells,” Journal of Immunological Methods, Vol. 248, No. , 2001, pp. 67-76. doi:10.1016/S0022-1759(00)00343-4
[11] E. J. Cheadle, D. E. Gilham, F. C. Thistlethwaite, J. A. Radford and R. E. Hawkins, “Killing of Non-Hodgkin Lymphoma Cells by Autologous CD19 Engineered T Cells,” British Journal of Haematology, Vol. 129, No. 3, 2005, pp. 322-332. doi:10.1111/j.1365-2141.2005.05456.x
[12] M. C. Gong, J. B. Latouche, A. Krause, W. D. Heston, N. H. Bander and M. Sadelain, “Cancer Patient T Cells Genetically Targeted to Prostate-Specific Membrane Antigen Specifically Lyse Prostate Cancer Cells and Release Cytokines in Response to Prostate-Specific Membrane Antigen,” Neoplasia, Vol. 1, No. 2, 1999, pp. 123-127. doi:10.1038/sj.neo.7900018
[13] N. M. Haynes, J. A. Trapani, M. W. Teng, J. T. Jackson, L. Cerruti, S. M. Jane, M. H. Kershaw, M. J. Smyth and P. K. Darcy, “Single-Chain Antigen Recognition Receptors That Costimulate Potent Rejection of Established Experimental Tumors,” Blood, Vol. 100, No. 10, 2002, pp. 3155-3163. doi:10.1182/blood-2002-04-10411
[14] B. Savoldo, C. M. Rooney, A. Di Stasi, H. Abken, A. Hombach, A. E. Foster, L. Zhang, H. E. Heslop, M. K. Brenner and G. Dotti, “Epstein Barr Virus-Specific Cytotoxic T Lymphocytes Expressing the Anti-CD30{Zeta} Artificial Chimeric T-Cell Receptor for Immunotherapy of Hodgkin’s Disease,” Blood, Vol. 110, No. 7, 2007, pp. 2620-2630. doi:10.1182/blood-2006-11-059139
[15] E. J. Cheadle, R. E. Hawkins, H. Batha, D. G. Rothwell, G. Ashton and D. E. Gilham, “Eradication of Established B-Cell Lymphoma by CD19-specific Murine T Cells is Dependent on Host Lymphopenic Environment and Can Be Mediated by CD4+ and CD8+ T Cells,” Journal of Immunotherapy, Vol. 32, No. 3, 2009, PP. 207-218. doi:10.1097/CJI.0b013e318194a921
[16] E. J. Cheadle, R. E. Hawkins, H. Batha, A. L. O’Neill, S. J. Dovedi and D. E. Gilham, “Natural Expression of the CD19 Antigen Impacts the Long-Term Engraftment but Not Antitumor Activity of CD19-Specific Engineered T Cells,” Journal of Immunotherapy, Vol. 184, No. 4, 2010, pp. 1885-1896. doi:10.4049/jimmunol.0901440
[17] L. M. Nadler, K. C. Anderson, G. Marti, M. Bates, E. Park, J. F. Daley and S. F. Schlossman, “B4, a Human B Lymphocyte-Associated Antigen Expressed on Normal, Mitogen-Activated, and Malignant B Lymphocytes,” Journal of Immunotherapy, Vol. 131, No. 1, 1983, pp. 244-250.
[18] F. M. Uckun, W. Jaszcz, J. L. Ambrus, A. S. Fauci, K. Gajl-Peczalska, C. W. Song, M. R. Wick, D. E. Myers, K. Waddick and J. A. Ledbetter, “Detailed Studies on Expression and Function of CD19 Surface Determinant by Using B43 Monoclonal Antibody and the Clinical Potential of Anti-CD19 Immunotoxins,” Blood, Vol. 71, No. 1, 1988, pp. 13-29.
[19] R. J. Brentjens, J. B. Latouche, E. Santos, F. Marti, M. C. Gong, C. Lyddane, P. D. King, S. Larson, M. Weiss, I. Riviere and M. Sadelain, “Eradication of Systemic B-Cell Tumors by Genetically Targeted Human T Lymphocytes Co-Stimulated by CD80 and Interleukin-15,” Nature Medicine, Vol. 9, No. 3, 2003, pp. 279-286. doi:10.1038/nm827
[20] L. J. Cooper, M. S. Topp, L. M. Serrano, S. Gonzalez, W. C. Chang, A. Naranjo, C. Wright, L. Popplewell, A. Raubitschek, S. J. Forman and M. C. Jensen, “T-Cell Clones Can Be Rendered Specific for CD19: Toward the Selective Augmentation of the Graft-versus-B-Lineage Leukemia Effect,” Blood, Vol. 101, No. 4, 2003, pp. 1637-1644. doi:10.1182/blood-2002-07-1989
[21] H. G. Drexler, “Recent Results on the Biology of Hodgkin and Reed-Sternberg Cells. I. Biopsy Material,” Leukemia & Lymphoma, Vol. 8, No. 4-5, 1992, pp. 283-313. doi:10.3109/10428199209051008
[22] H. G. Drexler, “Recent Results on the Biology of Hodgkin and Reed-Sternberg Cells. II. Continuous Cell Lines,” Leukemia & Lymphoma, Vol. 9, No. 1-2, 1993, pp. 1-25. doi:10.3109/10428199309148499
[23] H. Herbst, G. Tippelmann, I. Anagnostopoulos, J. Gerdes, R. Schwarting, T. Boehm, S. Pileri, D. B. Jones and H. Stein, “Immunoglobulin and T-Cell Receptor Gene Rearrangements in Hodgkin's Disease and Ki-1-Positive Anaplastic Large Cell Lymphoma: Dissociation between Phenotype and Genotype,” Leukemia Research, Vol. 13, No. 2, 1989, pp. 103-116. doi:10.1016/0145-2126(89)90134-3
[24] C. Schmid, L. Pan, T. Diss and P. G. Isaacson, “Expression of B-Cell Antigens by Hodgkin’s and Reed-Sternberg Cells,” The American Journal of Pathology, Vol. 139, No. 4, 1991, pp. 701-707.
[25] V. Diehl, H. H. Kirchner, H. Burrichter, H. Stein, C. Fonatsch, J. Gerdes, M. Schaadt, W. Heit, B. Uchanska-Ziegler, A. Ziegler, F. Heintz and K. Sueno, “Characteristics of Hodgkin’s Disease-Derived Cell Lines,” Cancer Treatment Reports, Vol. 66, No. 4, 1982, pp. 615-632.
[26] G. M. Wilkie, C. Taylor, M. M. Jones, D. M. Burns, M. Turner, D. Kilpatrick, P. L. Amlot, D. H. Crawford and T. Haque, “Establishment and Characterization of a Bank of Cytotoxic T Lymphocytes for Immunotherapy of Epstein-Barr Virus-Associated Diseases,” Journal of Immunotherapy, Vol. 27, No. 4, 2004, pp. 309-316. doi:10.1097/00002371-200407000-00007
[27] E. J. Cheadle, D. E. Gilham and R. E. Hawkins, “The Combination of Cyclophosphamide and Human T Cells Genetically Engineered to Target CD19 Can Eradicate Established B-Cell Lymphoma,” British Journal of Haematology, Vol. 142, No. 1, 2008, pp. 65-68. doi:10.1111/j.1365-2141.2008.07145.x
[28] T. Haque, P. L. Amlot, N. Helling, J. A. Thomas, P. Sweny, K. Rolles, A. K. Burroughs, H. G. Prentice and D. H. Crawford, “Reconstitution of EBV-Specific T Cell Immunity in Solid Organ Transplant Recipients,” Journal of Immunology, Vol. 160, No. 12, 1998, pp. 6204-6209.
[29] M. Kalos, B. L. Levine, D. L. Porter, S. Katz, S. A. Grupp, A. Bagg and C. H. June, “T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia,” Science Translational Medicine Home, Vol. 3, No. 95, 2011, p. 95ra73. doi:10.1126/scitranslmed.3002842
[30] D. L. Porter, B. L. Levine, M. Kalos, A. Bagg and C. H. June, “Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia,” The New England Journal of Medicine, Vol. 365, No. 8, 2011, pp. 725-733. doi:10.1056/NEJMoa1103849
[31] R. J. Brentjens, I. Riviere, J. H. Park, M. L. Davila, X. Wang, J. Stefanski, C. Taylor, R. Yeh, S. Bartido, O. Borquez-Ojeda, M. Olszewska, Y. Bernal, H. Pegram, M. Przybylowski, D. Hollyman, Y. Usachenko, D. Pirraglia, J. Hosey, E. Santos, E. Halton, P. Maslak, D. Scheinberg, J. Jurcic, M. Heaney, G. Heller, M. Frattini and M. Sadelain, “Safety and Persistence of Adoptively Transferred Autologous CD19-Targeted T Cells in Patients with Relapsed or Chemotherapy Refractory B-Cell Leukemias,” Blood, Vol. 118,
[32] J. N. Kochenderfer, M. E. Dudley, S. A. Feldman, W. H.Wilson, D. E. Spaner, I. Maric, M. Stetler-Stevenson, G. Q. Phan, M. S. Hughes, R. M. Sherry, J. C. Yang, U. S. Kammula, L. Devillier, R. Carpenter, D. A. Nathan, R. A. Morgan, C. Laurencot and S. A. Rosenberg, “B-Cell Depletion and Remissions of Malignancy along with Cytokine-Associated Toxicity in a Clinical Trial of Anti-CD19 Chimeric-Antigen-Receptor-Transduced T Cells,” Blood, Vol. 119, No. 12, 2012, pp. 2709-2720. doi:10.1182/blood-2011-10-384388

  
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