Integrated functional genomics approach for the design of patient-individual antitumor vaccines.

Our aim is to identify as many candidates as possible for tumor-associated T-cell epitopes in individual patients. First, we performed expression profiling of tumor and normal tissue to identify genes exclusively expressed or overexpressed in the tumor sample. Then, using mass spectrometry, we characterized up to 77 different MHC ligands from the same tumor sample. Several of the MHC ligands were derived from overexpressed gene products, one was derived from a proto-oncogene, and another was derived from a frameshift mutation. At least one was identified as an actual T-cell epitope. Thus, we could show that by combining these two analytic tools, it is possible to propose several candidates for peptide-based immunotherapy. We envision the use of this novel integrated functional genomics approach for the design of antitumor vaccines tailored to suit the needs of each patient.

[1]  H. Rackwitz,et al.  Adipophilin is a specific marker of lipid accumulation in diverse cell types and diseases , 1998, Cell and Tissue Research.

[2]  M Vingron,et al.  Identification and Classification of Differentially Expressed Genes in Renal Cell Carcinoma by Expression Profiling on a Global Human 31 , 500-Element cDNA Array , 2001 .

[3]  M. Satoh,et al.  Cancer-associated expression of glycolipid sulfotransferase gene in human renal cell carcinoma cells. , 1998, Cancer research.

[4]  H. Grey,et al.  Induction of anti-tumor cytotoxic T lymphocytes in normal humans using primary cultures and synthetic peptide epitopes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[5]  P. Coulie,et al.  Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. , 1997, Immunity.

[6]  K. Furge,et al.  Gene expression profiling of clear cell renal cell carcinoma: Gene identification and prognostic classification , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  M. Pfreundschuh,et al.  Serological analysis of human tumor antigens: molecular definition and implications. , 1997, Molecular medicine today.

[8]  C. Barnstable,et al.  Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens-new tools for genetic analysis , 1978, Cell.

[9]  P. Parham,et al.  Partial purification and some properties of BB7.2. A cytotoxic monoclonal antibody with specificity for HLA-A2 and a variant of HLA-A28. , 1981, Human immunology.

[10]  T. Uchida,et al.  Parathyroid hormone‐related protein is an independent prognostic factor for renal cell carcinoma , 1999, Cancer.

[11]  Odile Burlet-Schiltz,et al.  The Production of a New MAGE-3 Peptide Presented to Cytolytic T Lymphocytes by HLA-B40 Requires the Immunoproteasome , 2002, The Journal of experimental medicine.

[12]  P. Yaswen,et al.  Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[13]  F. Marshall,et al.  Expression profiling of renal epithelial neoplasms: a method for tumor classification and discovery of diagnostic molecular markers. , 2001, The American journal of pathology.

[14]  Jonathan J. Lewis,et al.  Immunization of cancer patients with autologous cancer‐derived heat shock protein gp96 preparations: A pilot study , 2000, International journal of cancer.

[15]  V. Engelhard,et al.  Phase I trial of a melanoma vaccine with gp100(280-288) peptide and tetanus helper peptide in adjuvant: immunologic and clinical outcomes. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[16]  Michael A. Choti,et al.  A Phosphatase Associated with Metastasis of Colorectal Cancer , 2001, Science.

[17]  J. Schultze,et al.  From cancer genomics to cancer immunotherapy: toward second-generation tumor antigens. , 2001, Trends in immunology.

[18]  R. Henderson,et al.  Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. , 1994, Science.

[19]  H. Rammensee,et al.  Cutting Edge: Characterization of Allorestricted and Peptide-Selective Alloreactive T Cells Using HLA-Tetramer Selection1 , 2001, The Journal of Immunology.

[20]  Jonathan W. Yewdell,et al.  Immunoproteasomes Shape Immunodominance Hierarchies of Antiviral Cd8+ T Cells at the Levels of T Cell Repertoire and Presentation of Viral Antigens , 2001, The Journal of experimental medicine.

[21]  Cécile Gouttefangeas,et al.  Identification of tumor‐associated MHC class I ligands by a novel T cell‐independent approach , 2000, European journal of immunology.

[22]  C. Figdor,et al.  The renal cell carcinoma-associated antigen G250 encodes a human leukocyte antigen (HLA)-A2.1-restricted epitope recognized by cytotoxic T lymphocytes. , 1999, Cancer research.

[23]  Mark M. Davis,et al.  Melanocyte Destruction after Antigen-Specific Immunotherapy of Melanoma , 2000, The Journal of experimental medicine.

[24]  D. N. Perkins,et al.  Probability‐based protein identification by searching sequence databases using mass spectrometry data , 1999, Electrophoresis.

[25]  Raymond B. Runyan,et al.  Expression of complete keratin filaments in mouse L cells augments cell migration and invasion. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[26]  P. Coulie,et al.  Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE‐3 and presented by HLA‐A1 , 1999, International journal of cancer.

[27]  P. Chomez,et al.  A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. , 1991, Science.

[28]  Philip J. R. Goulder,et al.  Phenotypic Analysis of Antigen-Specific T Lymphocytes , 1996, Science.

[29]  Dirk Schadendorf,et al.  Vaccination of melanoma patients with peptide- or tumorlysate-pulsed dendritic cells , 1998, Nature Medicine.

[30]  K. Hadeler,et al.  PAProC: a prediction algorithm for proteasomal cleavages available on the WWW , 2001, Immunogenetics.

[31]  G. Landberg,et al.  Cyclin‐D1 expression in human renal‐cell carcinoma , 1999, International journal of cancer.

[32]  K. Schmid,et al.  Differential expression of annexins I, II and IV in human tissues: an immunohistochemical study , 1998, Histochemistry and Cell Biology.

[33]  D. Jäger,et al.  Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[34]  L. Kanz,et al.  Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. , 2000 .

[35]  R. Offringa,et al.  The self peptide annexin II (208–223) presented by dendritic cells sensitizes autologous CD4+ T lymphocytes to recognize melanoma cells , 2001, Cancer Immunology, Immunotherapy.

[36]  Søren Buus,et al.  Tumor‐associated antigens identified by mRNA expression profiling induce protective anti‐tumor immunity , 2001, European journal of immunology.

[37]  F. Marincola,et al.  Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma , 1998, Nature Medicine.

[38]  Ferry Ossendorp,et al.  Efficient Identification of Novel Hla-A*0201–Presented Cytotoxic T Lymphocyte Epitopes in the Widely Expressed Tumor Antigen Prame by Proteasome-Mediated Digestion Analysis , 2001, The Journal of experimental medicine.

[39]  P. Coulie,et al.  A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[40]  H. Ragde,et al.  Evaluation of phase I/II clinical trials in prostate cancer with dendritic cells and PSMA peptides , 1998, The Prostate.

[41]  D. Lockhart,et al.  Expression monitoring by hybridization to high-density oligonucleotide arrays , 1996, Nature Biotechnology.

[42]  H. Stauss,et al.  Generation of human tumor‐reactive cytotoxic T cells against peptides presented by non‐self HLA class I molecules , 1998, European journal of immunology.

[43]  F. Triebel,et al.  A non-AUG-defined alternative open reading frame of the intestinal carboxyl esterase mRNA generates an epitope recognized by renal cell carcinoma-reactive tumor-infiltrating lymphocytes in situ. , 1999, Journal of immunology.

[44]  H. Rammensee,et al.  Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules , 1991, Nature.

[45]  Jian Ni,et al.  Cell Cycle Regulation by Galectin-12, a New Member of the Galectin Superfamily* , 2001, The Journal of Biological Chemistry.

[46]  E. Wang,et al.  Functional analysis of antigen-specific T lymphocytes by serial measurement of gene expression in peripheral blood mononuclear cells and tumor specimens. , 1999, Journal of immunology.

[47]  Ronald W. Davis,et al.  Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray , 1995, Science.

[48]  U. Şahin,et al.  Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices , 1999, Nature Biotechnology.

[49]  S. Altschul,et al.  A public database for gene expression in human cancers. , 1999, Cancer research.

[50]  M. Probst-Kepper,et al.  Processing of some antigens by the standard proteasome but not by the immunoproteasome results in poor presentation by dendritic cells. , 2000, Immunity.