A novel multi‐epitope vaccine from MMSA‐1 and DKK1 for multiple myeloma immunotherapy

The identification of novel tumour‐associated antigens is urgently needed to improve the efficacy of immunotherapy for multiple myeloma (MM). In this study, we identified a membrane protein MMSA‐1 (multiple myeloma special antigen‐1) that was specifically expressed in MM and exhibited significantly positive correlation with MM. We then identified HLA‐A*0201‐restricted MMSA‐1 epitopes and tested their cytotoxic T lymphocyte (CTL) response. The MMSA‐1 epitope SLSLLTIYV vaccine was shown to induce an obvious CTL response in vitro. To improve the immunotherapy, we constructed a multi‐epitope peptide vaccine by combining epitopes derived from MMSA‐1 and Dickkopf‐1 (DKK1). The effector T cells induced by multi‐epitope peptide vaccine‐loaded dendritic cells lysed U266 cells more effectively than MMSA‐1/DKK1 single‐epitope vaccine. In myeloma‐bearing severe combined immunodeficient mice, the multi‐epitope vaccine improved the survival rate significantly compared with single‐epitope vaccine. Consistently, multi‐epitope vaccine decreased the tumour volume greatly and alleviated bone destruction. The frequencies of CD4+ and CD8+ T cells was significantly increased in mouse blood induced by the multi‐epitope vaccine, indicating that it inhibits myeloma growth by changing T cell subsets and alleviating immune paralysis. This study identified a novel peptide from MMSA‐1 and the multi‐epitope vaccine will be used to establish appropriate individualized therapy for MM.

[1]  Yongchang Wei,et al.  MMSA-1 expression pattern in multiple myeloma and its clinical significance , 2016, Clinical and Experimental Medicine.

[2]  Oliver Kohlbacher,et al.  The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell-based immunotherapy. , 2015, Blood.

[3]  R. Zhu,et al.  Assessment of the Impact of Zoledronic Acid on Ovariectomized Osteoporosis Model Using Micro-CT Scanning , 2015, PloS one.

[4]  B. Liu,et al.  The development of potential antibody-based therapies for myeloma. , 2015, Blood reviews.

[5]  Di Chen,et al.  Anti-DKK1 antibody promotes bone fracture healing through activation of β-catenin signaling. , 2015, Bone.

[6]  Md. Faruk Hossain,et al.  Identification and validation of T-cell epitopes in outer membrane protein (OMP) of Salmonella typhi , 2014, Bioinformation.

[7]  Navid Nezafat,et al.  A novel multi-epitope peptide vaccine against cancer: an in silico approach. , 2014, Journal of theoretical biology.

[8]  N. Munshi,et al.  A Multiepitope of XBP1, CD138 and CS1 Peptides Induces Myeloma-Specific Cytotoxic T lymphocytes in T cells of Smoldering Myeloma Patients , 2014, Leukemia.

[9]  Fan Yang,et al.  MAGEC2, an epithelial-mesenchymal transition inducer, is associated with breast cancer metastasis , 2014, Breast Cancer Research and Treatment.

[10]  E. Warren,et al.  Immune escape from NY-ESO-1-specific T cell therapy via loss of heterozygosity in the MHC , 2014, Gene Therapy.

[11]  Y. He,et al.  Roles of brain and muscle ARNT‐like 1 and Wnt antagonist Dkk1 during osteogenesis of bone marrow stromal cells , 2013, Cell proliferation.

[12]  F. Zhou,et al.  Dickkopf-1 is a key regulator of myeloma bone disease: opportunities and challenges for therapeutic intervention. , 2013, Blood reviews.

[13]  V. Brusic,et al.  Identification of human leucocyte antigen (HLA)‐A*0201‐restricted cytotoxic T lymphocyte epitopes derived from HLA‐DOβ as a novel target for multiple myeloma , 2013, British journal of haematology.

[14]  O. Landgren,et al.  Evolving therapeutic paradigms for multiple myeloma: back to the future , 2013, Leukemia & lymphoma.

[15]  K. Anderson,et al.  Myeloma-Specific Multiple Peptides Able to Generate Cytotoxic T Lymphocytes: A Potential Therapeutic Application in Multiple Myeloma and Other Plasma Cell Disorders , 2012, Clinical Cancer Research.

[16]  Yanfeng Gao,et al.  Identification of a novel HLA-A2-restricted cytotoxic T lymphocyte epitope from cancer-testis antigen PLAC1 in breast cancer , 2012, Amino Acids.

[17]  T. Shen,et al.  HER2-specific T lymphocytes kill both trastuzumab-resistant and trastuzumab-sensitive breast cell lines in vitro , 2012, Chinese journal of cancer research = Chung-kuo yen cheng yen chiu.

[18]  A. Nagler,et al.  Novel Strategies for Immunotherapy in Multiple Myeloma: Previous Experience and Future Directions , 2012, Clinical & developmental immunology.

[19]  J. Greiner,et al.  Immunogenic Targets for Specific Immunotherapy in Multiple Myeloma , 2012, Clinical & developmental immunology.

[20]  Jinghong Zhao,et al.  Computational prediction and experimental assessment of an HLA-A*0201-restricted cytotoxic T lymphocyte epitope from neutral endopeptidase , 2012, Immunologic Research.

[21]  N. Munshi,et al.  Latest advances and current challenges in the treatment of multiple myeloma , 2012, Nature Reviews Clinical Oncology.

[22]  I. Bruns,et al.  The level of minimal residual disease in the bone marrow of patients with multiple myeloma before high-dose therapy and autologous blood stem cell transplantation is an independent predictive parameter. , 2012, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[23]  E. Celis,et al.  Design of immunogenic and effective multi-epitope DNA vaccines for melanoma , 2012, Cancer Immunology, Immunotherapy.

[24]  L. Kwak,et al.  Active vaccination with Dickkopf-1 induces protective and therapeutic antitumor immunity in murine multiple myeloma. , 2012, Blood.

[25]  M. Caligiuri,et al.  IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect. , 2011, Blood.

[26]  N. Munshi,et al.  Identification of novel myeloma-specific XBP1 peptides able to generate cytotoxic T lymphocytes: A potential therapeutic application in multiple myeloma , 2011, Leukemia.

[27]  B. Barlogie,et al.  Epigenetic modulation of MAGE-A3 antigen expression in multiple myeloma following treatment with the demethylation agent 5-azacitidine and the histone deacetlyase inhibitor MGCD0103. , 2011, Cytotherapy.

[28]  Kenneth C. Anderson,et al.  Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors , 2011, The Journal of Immunology.

[29]  Junnian Zheng,et al.  Identification of HLA-A*0201-restricted cytotoxic T lymphocyte epitope from proliferating cell nuclear antigen , 2011, Tumor Biology.

[30]  Yongchang Wei,et al.  Peptide-based immunotherapy for multiple myeloma: current approaches. , 2010, Vaccine.

[31]  H. Komatsu.  [Antibody therapy in cancer]. , 2010, Nihon rinsho. Japanese journal of clinical medicine.

[32]  G. Peoples,et al.  A new era in anticancer peptide vaccines , 2010, Cancer.

[33]  P. Bourin,et al.  DKK1 correlates with response and predicts rapid relapse after autologous stem cell transplantation in Multiple Myeloma , 2010, European journal of haematology.

[34]  Michael L. Wang,et al.  Myeloma cell line-derived, pooled heat shock proteins as a universal vaccine for immunotherapy of multiple myeloma. , 2009, Blood.

[35]  Michael L. Wang,et al.  Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma. , 2007, Blood.

[36]  T. Ørntoft,et al.  Differential expression of DHHC9 in microsatellite stable and instable human colorectal cancer subgroups , 2007, British Journal of Cancer.

[37]  W. Zhao,et al.  Serological identification and bioinformatics analysis of immunogenic antigens in multiple myeloma , 2006, Cancer Immunology, Immunotherapy.

[38]  Ming Liu,et al.  [Immunological screening for multiple myeloma-associated antigens and their bioinformatics analysis]. , 2006, Zhongguo shi yan xue ye xue za zhi.

[39]  Jin Xie,et al.  Targeting Heat Shock Proteins for Immunotherapy in Multiple Myeloma: Generation of Myeloma-Specific CTLs Using Dendritic Cells Pulsed with Tumor-Derived gp96 , 2005, Clinical Cancer Research.

[40]  F. Zhan,et al.  The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. , 2003, The New England journal of medicine.

[41]  J. Baatz,et al.  Cross-reactivity between HLA-A2-restricted FLU-M1:58–66 and HIV p17 GAG:77–85 epitopes in HIV-infected and uninfected individuals , 2003, Journal of Translational Medicine.

[42]  H. Rammensee,et al.  SYFPEITHI: database for MHC ligands and peptide motifs , 1999, Immunogenetics.

[43]  M. Brigden.  Clinical utility of the erythrocyte sedimentation rate. , 1999, American family physician.

[44]  C. Coltman,et al.  Prognostic value of pretreatment serum beta 2 microglobulin in myeloma: a Southwest Oncology Group Study. , 1990, Blood.

[45]  Z. Trajanoski,et al.  Somatically mutated tumor antigens in the quest for a more efficacious patient-oriented immunotherapy of cancer , 2014, Cancer Immunology, Immunotherapy.

[46]  Xing-mei Cao,et al.  [The research on the expression and localization of multiple myeloma associated antigen MMSA-1]. , 2012, Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology.

[47]  J. Roliński,et al.  Generation of dendritic cells from human peripheral blood monocytes--comparison of different culture media. , 2005, Folia histochemica et cytobiologica.

[48]  L. Old,et al.  Immunogenetics of human cell surface differentiation. , 1989, Annual review of immunology.