Cancer-testis antigen SLLP1 represents a promising target for the immunotherapy of multiple myeloma

Journal of Translational Medicine

Djordje Atanackovic²  Tim Luetkens¹  Nicolaus Kröger³  Katrin Bartels¹  Nesrine Lajmi¹  Johanna Heise¹  Sara Yousef³ 

[1] Oncology/Hematology/Bone Marrow Transplantation with the Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Multiple Myeloma Program and Cancer Immunotherapy, Division of Hematology and Hematologic Malignancies, University of Utah/Huntsman Cancer Institute, Room HCI 4265, 2000 Circle of Hope Drive, Salt Lake City 84112, UT, USA;Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

关键词: Adoptive cell transfer;    Immunotherapy;    Tumor immunology;    Multiple myeloma;    SLLP1;    Cancer-testis antigens;   

Others  :  1228114
DOI  :  10.1186/s12967-015-0562-5

 received in 2015-01-11, accepted in 2015-06-03,  发布年份 2015

【 摘 要 】

Background

Most patients with multiple myeloma (MM) will relapse after an initial response and eventually succumb to their disease. This is due to the persistence of chemotherapy-resistant tumor cells in the patients’ bone marrow (BM) and immunotherapeutic approaches could contribute to eradicating these remaining cells. We evaluated SLLP1 as a potentialimmunotherapeutic target for MM.

Methods

We determined SLLP1 expression in myeloma cell lines and 394 BM samples from myeloma patients (n = 177) and BM samples from healthy donors (n = 11). 896 blood samples and 64 BM samples from myeloma patients (n = 263) and blood from healthy donors (n = 112) were analyzed for anti-SLLP1 antibodies. Seropositive patients were evaluated regarding SLLP1-specific T cells.

Results

Most cell lines showed SLLP1 RNA and protein expression while it was absent from normal BM. Of 177 patients 41% evidenced SLLP1 expression at least once during the course of their disease and 44% of newly diagnosed patients were SLLP1-positive. Expression of SLLP1 was associated with adverse cytogenetics and with negative prognostic factors including the patient’s age, number of BM-infiltrating plasma cells, serum albumin, β ₂ -microglobulin, creatinine, and hemoglobin. Among patients treated with allogeneic stem cell transplantation those with SLLP1 expression showed a trend towards a reduced overall survival. Spontaneous anti-SLLP humoral immunity was detectable in 9.5% of patients but none of the seropositive patients evidenced SLLP1-specific T cells. However, antigen-specific T cells could readily be induced in vitro after stimulation with SLLP1.

Conclusions

SLLP1 represents a promising target for the immunotherapy of MM, in particular for the adoptive transfer of T cell receptor-transduced T cells.

【 授权许可】

   
2015 Yousef et al.

【 图 表 】

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【 参考文献 】

• [1]Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S et al.. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014; 28:1122-1128.
• [2]Kim D, Park CY, Medeiros BC, Weissman IL. CD19-CD45 low/− CD38 high/CD138+ plasma cells enrich for human tumorigenic myeloma cells. Leukemia. 2012; 26:2530-2537.
• [3]Chaidos A, Barnes CP, Cowan G, May PC, Melo V, Hatjiharissi E et al.. Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma. Blood. 2013; 121:318-328.
• [4]Matsui W, Borrello I, Mitsiades C. Autologous stem cell transplantation and multiple myeloma cancer stem cells. Biol Blood Marrow Transplant. 2012; 18:S27-S32.
• [5]Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L et al.. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010; 28:2077-2084.
• [6]Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE et al.. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol. 2013; 31:2540-2547.
• [7]Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA et al.. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008; 112:4017-4023.
• [8]Ferrero S, Ladetto M, Drandi D, Cavallo F, Genuardi E, Urbano M et al.. Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics’ impact on survival. Leukemia. 2014; 29:689-695.
• [9]Whitehurst AW. Cause and consequence of cancer/testis antigen activation in cancer. Annu Rev Pharmacol Toxicol. 2014; 54:251-272.
• [10]Mandal A, Klotz KL, Shetty J, Jayes FL, Wolkowicz MJ, Bolling LC et al.. SLLP1, a unique, intra-acrosomal, non-bacteriolytic, c lysozyme-like protein of human spermatozoa. Biol Reprod. 2003; 68:1525-1537.
• [11]Wang Z, Zhang Y, Mandal A, Zhang J, Giles FJ, Herr JC et al.. The spermatozoa protein, SLLP1, is a novel cancer-testis antigen in hematologic malignancies. Clin Cancer Res. 2004; 10:6544-6550.
• [12]Atanackovic D, Luetkens T, Hildebrandt Y, Arfsten J, Bartels K, Horn C et al.. Longitudinal analysis and prognostic effect of cancer-testis antigen expression in multiple myeloma. Clin Cancer Res. 2009; 15:1343-1352.
• [13]Atanackovic D, Hildebrandt Y, Templin J, Cao Y, Keller C, Panse J et al.. Role of interleukin 16 in multiple myeloma. J Natl Cancer Inst. 2012; 104:1005-1020.
• [14]Reinhard H, Yousef S, Luetkens T, Fehse B, Berdien B, Kroger N et al.. Cancer-testis antigen MAGE-C2/CT10 induces spontaneous CD4+ and CD8+ T-cell responses in multiple myeloma patients. Blood Cancer J. 2014; 4:e212.
• [15]Atanackovic D, Matsuo M, Ritter E, Mazzara G, Ritter G, Jager E et al.. Monitoring CD4+ T cell responses against viral and tumor antigens using T cells as novel target APC. J Immunol Methods. 2003; 278:57-66.
• [16]Berdien B, Reinhard H, Meyer S, Spock S, Kroger N, Atanackovic D et al.. Influenza virus-specific TCR-transduced T cells as a model for adoptive immunotherapy. Hum Vaccin Immunother. 2013; 9:1205-1216.
• [17]Han M, Harrison L, Kehn P, Stevenson K, Currier J, Robinson MA. Invariant or highly conserved TCR alpha are expressed on double-negative (CD3+CD4−CD8−) and CD8+ T cells. J Immunol. 1999; 163:301-311.
• [18]Currier JR, Deulofeut H, Barron KS, Kehn PJ, Robinson MA. Mitogens, superantigens, and nominal antigens elicit distinctive patterns of TCRB CDR3 diversity. Hum Immunol. 1996; 48:39-51.
• [19]Gnjatic S, Atanackovic D, Jager E, Matsuo M, Selvakumar A, Altorki NK et al.. Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses. Proc Natl Acad Sci USA. 2003; 100:8862-8867.
• [20]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.
• [21]Luetkens T, Schafhausen P, Uhlich F, Stasche T, Akbulak R, Bartels BM et al.. Expression, epigenetic regulation, and humoral immunogenicity of cancer-testis antigens in chronic myeloid leukemia. Leuk Res. 2010; 34:1647-1655.
• [22]GTExPortal. http://www.gtexportal.org/home/gene/SPACA3. Accessed 12 April 2015
• [23]Atanackovic D, Luetkens T, Kloth B, Fuchs G, Cao Y, Hildebrandt Y et al.. Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia. Am J Hematol. 2011; 86:918-922.
• [24]Atanackovic D, Hildebrandt Y, Jadczak A, Cao Y, Luetkens T, Meyer S et al.. Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells. Haematologica. 2010; 95:785-793.
• [25]Nardiello T, Jungbluth AA, Mei A, Diliberto M, Huang X, Dabrowski A et al.. MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin. Clin Cancer Res. 2011; 17:4309-4319.
• [26]Donato ML, Siegel DS, Vesole DH, McKiernan P, Nyirenda T, Pecora AL et al.. The graft-versus-myeloma effect: chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation. Biol Blood Marrow Transplant. 2014; 20:1211-1216.
• [27]Galo-Hooker EG, Ruiz-Delgado GJ, Zamora-Ortiz G, Velazquez-Sanchez-de-Cima S, Ruiz-Arguelles GJ. In pursuit of the graft-versus-myeloma effect: a single institution experience. Hematology. 2013; 18:89-92.
• [28]Sahebi F, Shen Y, Thomas SH, Rincon A, Murata-Collins J, Palmer J et al.. Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long-term follow-up study. Br J Haematol. 2013; 160:199-206.
• [29]Jager E, Nagata Y, Gnjatic S, Wada H, Stockert E, Karbach J et al.. Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses. Proc Natl Acad Sci USA. 2000; 97:4760-4765.
• [30]Luetkens T, Kobold S, Cao Y, Ristic M, Schilling G, Tams S et al.. Functional autoantibodies against SSX-2 and NY-ESO-1 in multiple myeloma patients after allogeneic stem cell transplantation. Cancer Immunol Immunother. 2014; 63:1151-1162.
• [31]Moeller I, Spagnoli GC, Finke J, Veelken H, Houet L. Uptake routes of tumor-antigen MAGE-A3 by dendritic cells determine priming of naive T-cell subtypes. Cancer Immunol Immunother. 2012; 61:2079-2090.
• [32]Noguchi T, Kato T, Wang L, Maeda Y, Ikeda H, Sato E et al.. Intracellular tumor-associated antigens represent effective targets for passive immunotherapy. Cancer Res. 2012; 72:1672-1682.
• [33]Dhodapkar KM, Krasovsky J, Williamson B, Dhodapkar MV. Antitumor monoclonal antibodies enhance cross-presentation ofcCellular antigens and the generation of myeloma-specific killer T cells by dendritic cells. J Exp Med. 2002; 195:125-133.
• [34]Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen YT. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev. 2002; 188:22-32.
• [35]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.
• [36]Robbins PF, Kassim SH, Tran TL, Crystal JS, Morgan RA, Feldman SA et al.. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T cell receptor: long term follow up and correlates with response. Clin Cancer Res. 2014; 21:1019-1027.
• [37]Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z et al.. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013; 36:133-151.