Abstract
Adoptive immunotherapy of tumors with T cells specific for the cancer-testis antigen NY-ESO-1 has shown great promise in preclinical models and in early stage clinical trials. Tumor persistence or recurrence after NY-ESO-1-specific therapy occurs, however, and the mechanisms of recurrence remain poorly defined. In a murine xenograft model of NY-ESO-1+ multiple myeloma, we observed tumor recurrence after adoptive transfer of CD8+ T cells genetically redirected to the prototypic NY-ESO-1157-165 peptide presented by HLA-A*02:01. Analysis of the myeloma cells that had escaped from T-cell control revealed intact expression of NY-ESO-1 and B2M, but selective, complete loss of HLA-A*02:01 expression from the cell surface. Loss of heterozygosity (LOH) in the major histocompatibility complex (MHC) involving the HLA-A locus was identified in the tumor cells, and further analysis revealed selective loss of the allele encoding HLA-A*02:01. Although LOH involving the MHC has not been described in myeloma patients with persistent or recurrent disease after immune therapies such as allogeneic hematopoietic cell transplantation (HCT), it has been described in patients with acute myelogenous leukemia who relapsed after allogeneic HCT. These results suggest that MHC loss should be evaluated in patients with myeloma and other cancers who relapse after adoptive NY-ESO-1-specific T-cell therapy.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006; 314: 126–129.
Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 2011; 29: 917–924.
Rapoport AP, Stadtmauer EA, Vogl DT, Weiss BM, Binder-Scholl GK, Brewer JE et al. Adoptive transfer of gene-modified T-cells engineered to express high-affinity TCRs for cancer-testis antigens (CTAs) NY-ESO-1 or Lage-1, in MM patients post auto-SCT. ASH Annu Meet Abstr 2012; 120: 472.
Porter DL, Kalos M, Zheng Z, Levine B, June C . Chimeric antigen receptor therapy for B-cell malignancies. J Cancer 2011; 2: 331–332.
Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5: 177ra38.
Porter DL, Levine BL, Kalos M, Bagg A, June CH . Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365: 725–733.
Chapuis AG, Ragnarsson GB, Nguyen HN, Chaney CN, Pufnock JS, Schmitt TM et al. Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients. Sci Transl Med 2013; 5: 174ra27.
Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res 2013; 19: 2048–2060.
Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 2011; 118: 6050–6056.
Clay TM, Custer MC, Sachs J, Hwu P, Rosenberg SA, Nishimura MI . Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J Immunol 1999; 163: 507–513.
Cooper LJ, Kalos M, Lewinsohn DA, Riddell SR, Greenberg PD . Transfer of specificity for human immunodeficiency virus type 1 into primary human T lymphocytes by introduction of T-cell receptor genes. J Virol 2000; 74: 8207–8212.
Fujio K, Misaki Y, Setoguchi K, Morita S, Kawahata K, Kato I et al. Functional reconstitution of class II MHC-restricted T cell immunity mediated by retroviral transfer of the alpha beta TCR complex. J Immunol 2000; 165: 528–532.
Johnson LA, Heemskerk B, Powell Jr. DJ, Cohen CJ, Morgan RA, Dudley ME et al. Gene transfer of tumor-reactive TCR confers both high avidity and tumor reactivity to nonreactive peripheral blood mononuclear cells and tumor-infiltrating lymphocytes. J Immunol 2006; 177: 6548–6559.
Moss PA . Redirecting T cell specificity by TCR gene transfer. Nat Immunol 2001; 2: 900–901.
Schaft N, Willemsen RA, de Vries J, Lankiewicz B, Essers BW, Gratama JW et al. Peptide fine specificity of anti-glycoprotein 100 CTL is preserved following transfer of engineered TCR alpha beta genes into primary human T lymphocytes. J Immunol 2003; 170: 2186–2194.
Wang G, Chopra RK, Royal RE, Yang JC, Rosenberg SA, Hwu P . AT cell-independent antitumor response in mice with bone marrow cells retrovirally transduced with an antibody/Fc-gamma chain chimeric receptor gene recognizing a human ovarian cancer antigen. Nat Med 1998; 4: 168–172.
Jena B, Dotti G, Cooper LJ . Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor. Blood 2010; 116: 1035–1044.
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368: 1509–1518.
Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011; 3: 95ra73.
Rubinstein MP, Kadima AN, Salem ML, Nguyen CL, Gillanders WE, Nishimura MI et al. Transfer of TCR genes into mature T cells is accompanied by the maintenance of parental T cell avidity. J Immunol 2003; 170: 1209–1217.
Schuberth PC, Jakka G, Jensen SM, Wadle A, Gautschi F, Haley D et al. Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma. Gene Ther 2013; 20: 386–395.
Atanackovic D, Arfsten J, Cao Y, Gnjatic S, Schnieders F, Bartels K et al. Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation. Blood 2007; 109: 1103–1112.
Condomines M, Hose D, Raynaud P, Hundemer M, De Vos J, Baudard M et al. Cancer/testis genes in multiple myeloma: expression patterns and prognosis value determined by microarray analysis. J Immunol 2007; 178: 3307–3315.
Dhodapkar MV, Osman K, Teruya-Feldstein J, Filippa D, Hedvat CV, Iversen K et al. Expression of cancer/testis (CT) antigens MAGE-A1, MAGE-A3, MAGE-A4, CT-7, and NY-ESO-1 in malignant gammopathies is heterogeneous and correlates with site, stage and risk status of disease. Cancer Immun 2003; 3: 9.
Jungbluth AA, Ely S, DiLiberto M, Niesvizky R, Williamson B, Frosina D et al. The cancer-testis antigens CT7 (MAGE-C1) and MAGE-A3/6 are commonly expressed in multiple myeloma and correlate with plasma-cell proliferation. Blood 2005; 106: 167–174.
van Duin M, Broyl A, de Knegt Y, Goldschmidt H, Richardson PG, Hop WC et al. Cancer testis antigens in newly diagnosed and relapse multiple myeloma: prognostic markers and potential targets for immunotherapy. Haematologica 2011; 96: 1662–1669.
Carbone E, Neri P, Mesuraca M, Fulciniti MT, Otsuki T, Pende D et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood 2005; 105: 251–258.
Crucian BE, Moscinski LC, Androlewicz M, Ballester OF, Widen RH, Yu H . Assessment of intracellular TAP-1 and TAP-2 in conjunction with surface MHC class I in plasma cells from patients with multiple myeloma. Br J Haematol 1997; 98: 426–432.
Yi Q, Dabadghao S, Osterborg A, Bergenbrant S, Holm G . Myeloma bone marrow plasma cells: evidence for their capacity as antigen-presenting cells. Blood 1997; 90: 1960–1967.
Levine BL, Rapoport AP, Stadtmauer EA, Vogl DT, Weiss B, Binder-Scholl GK et al. Adoptive transfer of gene-modified T-cells engineered to express high-affinity TCR's for cancer-testis antigens NY-ESO-1 or LAGE-1, in multiple myeloma (MM) patients post-autologous hematopoietic stem cell transplant (ASCT). Cytotherapy 2013; 15: S13.
Robbins PF, Li YF, El-Gamil M, Zhao Y, Wargo JA, Zheng Z et al. Single and dual amino-acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. J Immunol 2008; 180: 6116–6131.
McCormack E, Adams KJ, Hassan NJ, Kotian A, Lissin NM, Sami M et al. Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors. Cancer Immunol Immunother 2013; 62: 773–785.
Garcia-Lora A, Algarra I, Garrido F . MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol 2003; 195: 346–355.
Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med 2009; 361: 478–488.
Villalobos IB, Takahashi Y, Akatsuka Y, Muramatsu H, Nishio N, Hama A et al. Relapse of leukemia with loss of mismatched HLA resulting from uniparental disomy after haploidentical hematopoietic stem cell transplantation. Blood 2010; 115: 3158–3161.
Bethge WA, Haegele M, Faul C, Lang P, Schumm M, Bornhauser M et al. Haploidentical allogeneic hematopoietic cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion: fast engraftment and low toxicity. Exp Hematol 2006; 34: 1746–1752.
Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641–650.
Nonami A, Miyamoto T, Kuroiwa M, Kunisaki Y, Kamezaki K, Takenaka K et al. Successful treatment of primary plasma cell leukaemia by allogeneic stem cell transplantation from haploidentical sibling. Jpn J Clin Oncol 2007; 37: 969–972.
Zomas A, Stefanoudaki K, Fisfis M, Papadaki T, Mehta J . Graft-versus-myeloma after donor leukocyte infusion: maintenance of marrow remission but extramedullary relapse with plasmacytomas. Bone Marrow Transplant 1998; 21: 1163–1165.
Alyea E, Weller E, Schlossman R, Canning C, Webb I, Doss D et al. T-cell—depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 2001; 98: 934–939.
Bellucci R, Alyea EP, Weller E, Chillemi A, Hochberg E, Wu CJ et al. Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma. Blood 2002; 99: 4610–4617.
El-Cheikh J, Crocchiolo R, Furst S, Ladaique P, Castagna L, Faucher C et al. Lenalidomide plus donor-lymphocytes infusion after allogeneic stem-cell transplantation with reduced-intensity conditioning in patients with high-risk multiple myeloma. Exp Hematol 2012; 40: 521–527.
Lokhorst HM, Schattenberg A, Cornelissen JJ, van Oers MH, Fibbe W, Russell I et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol 2000; 18: 3031–3037.
Orsini E, Alyea EP, Chillemi A, Schlossman R, McLaughlin S, Canning C et al. Conversion to full donor chimerism following donor lymphocyte infusion is associated with disease response in patients with multiple myeloma. Biol Blood Marrow Transplant 2000; 6: 375–386.
Riddell SR, Greenberg PD . The use of anti-CD3 and anti-CD28 monoclonal antibodies to clone and expand human antigen-specific T cells. J Immunol Methods 1990; 128: 189–201.
Chou J, Voong LN, Mortales CL, Towlerton AM, Pollack SM, Chen X et al. Epigenetic modulation to enable antigen-specific T-cell therapy of colorectal cancer. J Immunother 2012; 35: 131–141.
Brehm MA, Racki WJ, Leif J, Burzenski L, Hosur V, Wetmore A et al. Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rgamma null mice is enhanced by transgenic expression of membrane-bound human SCF. Blood 2012; 119: 2778–2788.
Ramal LM, Maleno I, Cabrera T, Collado A, Ferron A, Lopez-Nevot MA et al. Molecular strategies to define HLA haplotype loss in microdissected tumor cells. Hum Immunol 2000; 61: 1001–1012.
Acknowledgements
We thank Melissa Comstock and LaKeisha Perkins of the FHCRC NOD/Scid Core Facility for their assistance with the murine xenograft studies. The authors also thank the patients who have donated their blood and tissues for our work. These studies were supported by the J. Orin Edson Fund for Immunotherapy, a Senior Research Award from the Multiple Myeloma Research Foundation (to EHW), and NIH grants P30 CA015704-34, P30 DK56465 PI: B. Torok-Storb, and 5T32HL007093-39.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on Gene Therapy website
Supplementary information
Rights and permissions
About this article
Cite this article
Klippel, Z., Chou, J., Towlerton, A. et al. Immune escape from NY-ESO-1-specific T-cell therapy via loss of heterozygosity in the MHC. Gene Ther 21, 337–342 (2014). https://doi.org/10.1038/gt.2013.87
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gt.2013.87
Keywords
This article is cited by
-
The landscape of T cell antigens for cancer immunotherapy
Nature Cancer (2023)
-
Unleashing the immune response to NY-ESO-1 cancer testis antigen as a potential target for cancer immunotherapy
Journal of Translational Medicine (2020)
-
Current and New Therapeutic Strategies for Relapsed and Refractory Multiple Myeloma: An Update
Drugs (2018)
-
Therapeutic targeting of naturally presented myeloperoxidase-derived HLA peptide ligands on myeloid leukemia cells by TCR-transgenic T cells
Leukemia (2014)