NY-ESO-1 is highly expressed in poor-prognosis multiple myeloma and induces spontaneous humoral and cellular immune responses

University of Arkansas at Little Rock, Little Rock, Arkansas, United States
Blood (Impact Factor: 10.43). 06/2005; 105(10):3939-44. DOI: 10.1182/blood-2004-09-3707
Source: PubMed

ABSTRACT The presence of a metaphase cytogenetic abnormality (CA) is the key negative predictor of outcome in patients with multiple myeloma (MM). Gene expression profiling (GEP) of such patients showed increased expression of NY-ESO-1 compared to patients with normal cytogenetics (60% versus 31%; P = .004). NY-ESO-1 was also highly expressed in relapsing MM especially patients with CA (100% versus 60.7%; P < .001). GEP findings were confirmed at the protein level by immunostaining of marrow biopsies for NY-ESO-1. We detected spontaneous NY-ESO-1-specific antibodies by enzyme-linked immunosorbent assay in 33% of patients with NY-ESO-1+ MM, especially in CA patients (9 of 13; 70%), but in none of the NY-ESO-1- patients with MM (n = 27) or healthy donors (n = 21). Spontaneous NY-ESO-1(157-165)-specific T cells (0.2%-0.6% of CD8+ T cells) were found in the peripheral blood of NY-ESO-1+ MM with HLA-A*0201/NY-ESO-1(157-165) tetramers. These NY-ESO-1-specific T cells, when expanded, killed primary MM cells (50% lysis, effector-target [E/T] ratio, 10:1). Our data demonstrate that NY-ESO-1 is frequently expressed in MM with CA and is capable of eliciting spontaneous humoral and T-cell immunity. The pool of NY-ESO-1-specific cytotoxic T cells expands easily on NY-ESO-1 peptide stimulation and is functionally active. NY-ESO-1 should therefore be an ideal tumor target antigen for immunotherapy of patients with poor-prognosis MM.

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Available from: Guido Tricot, Aug 24, 2015
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    • "ª 2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 158, 700–711 research paper broad range of cellular and humoral immune responses. In myeloma, several reports have described sporadic overexpression of CTA and accompanying CTA-specific T cell and B cell responses (Lim et al, 2001; Wang et al, 2003; Jungbluth et al, 2005; Van Rhee et al, 2005; Condomines et al, 2007). Induced CTA alloreactivity has also been reported in MM patients undergoing allografting, possibly associated with freedom from relapse (Atanackovic et al, 2007). "
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    ABSTRACT: Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens (CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine (Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza-Rev and cryopreserved. Subsequent stem cell mobilization was followed by high-dose melphalan and SCT. Autologous lymphocyte infusion (ALI) was performed in the second month following transplantation. Fourteen patients have completed the investigational therapy; autologous lymphocytes were collected from all of the patients. Thirteen patients have successfully completed SCT and 11 have undergone ALI. Six patients tested have demonstrated CTA up-regulation in either unfractionated bone marrow (n = 4) or CD138+ cells (n = 2). CTA (CTAG1B)-specific T cell response has been observed in all three patients tested and persists following SCT. Epigenetic induction of an adaptive immune response to cancer testis antigens is safe and feasible in MM patients undergoing SCT.
    British Journal of Haematology 07/2012; 158(6):700-11. DOI:10.1111/j.1365-2141.2012.09225.x · 4.96 Impact Factor
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    • "NY-ESO-specific CTLs generated from patients with MM were shown to kill primary myeloma cells, normal cells pulsed with a NY-ESO-1 peptide, but not normal cells pulsed with an irrelevant peptide. Spontaneous humoral and CD8− T cell-mediated responses to NY-ESO-1 have been identified in patients with advanced disease [99] [124] [126]. Vaccination strategies targeting NY-ESO-1 may be effective at inducing specific antimyeloma immunity, and a clinical trial evaluating the efficacy of an NY-ESO peptide vaccination given in conjunction with GM-CSF is underway [99]. "
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    ABSTRACT: Multiple myeloma (MM) is a life-threatening haematological malignancy for which standard therapy is inadequate. Autologous stem cell transplantation is a relatively effective treatment, but residual malignant sites may cause relapse. Allogeneic transplantation may result in durable responses due to antitumour immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-versus-host disease remain a challenge. Recent advances in understanding the interaction between the immune system of the patient and the malignant cells are influencing the design of clinically more efficient study protocols for MM. Cellular immunotherapy using specific antigen-presenting cells (APCs), to overcome aspects of immune incompetence in MM patients, has received great attention, and numerous clinical trials have evaluated the potential for dendritic cell (DC) vaccines as a novel immunotherapeutic approach. This paper will summarize the data investigating aspects of immunity concerning MM, immunotherapy for patients with MM, and strategies, on the way, to target the plasma cell more selectively. We also include the MM antigens and their specific antibodies that are of potential use for MM humoral immunotherapy, because they have demonstrated the most promising preclinical results.
    Clinical and Developmental Immunology 05/2012; 2012:753407. DOI:10.1155/2012/753407 · 2.93 Impact Factor
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    • "Spontaneous antibodies and T lymphocytes directed against NY-ESO-1 were detected in MM patients. After being expanded by autologous antigen presenting cells (APCs) pulsed with NY-ESO-1-derived peptide analog, the specific CTLs were able to lyse primary MM cells [54]. Ropporin is a novel CTA identified in 2007 [34]. "
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    ABSTRACT: Multiple myeloma remains an incurable disease although the prognosis has been improved by novel therapeutics and agents recently. Relapse occurs in the majority of patients and becomes fatal finally. Immunotherapy might be a powerful intervention to maintain a long-lasting control of minimal residual disease or to even eradicate disseminated tumor cells. Several tumor-associated antigens have been identified in patients with multiple myeloma. These antigens are expressed in a tumor-specific or tumor-restricted pattern, are able to elicit immune response, and thus could serve as targets for immunotherapy. This review discusses immunogenic antigens with therapeutic potential for multiple myeloma.
    Clinical and Developmental Immunology 05/2012; 2012(7378):820394. DOI:10.1155/2012/820394 · 2.93 Impact Factor
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