Skip to main content

Tumor Antigen Discovery With T Cells

  • Chapter
Handbook of Cancer Vaccines

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Studies first carried out in the early 1980s demonstrated that incubation of tumorinfiltrating lymphocytes (TILs) with high doses of interleukin-2 (IL-2) resulted in the generation of CD8+ cytotoxic T cells (CTL) that recognized tumor cells in a major histocompatibility complex (MHC)-restricted manner. This procedure resulted in the generation of tumor-reactive T cells from about 50% of patients with melanoma and a smaller percentage of patients bearing other malignancies. The in vitro sensitization of peripheral blood mononuclear cells (PBMCs) from cancer patients with autologous or human leukocyte antigen (HLA)-matched allogeneic tumor cells in mixed lymphocyte tumor cultures (MLTCs) also resulted in the generation of tumor-reactive T cells. These cells as well as the tumor-reactive TIL-lysed tumor and released a variety of cytokines including interferon-γ (IFN-γ), granulocyte macrophage colony-stimulating factor (GM-CSF), or tumor necrosis factor-α (TNF-α) in response to human leukocyte antigen (HLA)-matched tumor targets. Tumor-reactive class II restricted T cells have also been identified in a significant percentage of the cultures of sensitized PBMC or TIL cultures containing class I—restricted tumor-reactive T cells.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991; 254, 1643–1647

    Article  PubMed  Google Scholar 

  2. Rammensee H, Bachmann J, Emmerich NP, Bachor OA, Stevanovic S. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 1999; 50:213–219.

    Article  PubMed  CAS  Google Scholar 

  3. Sette A, Vitiello A, Reherman B, Fowler P, Nayersina R, Kast WM, et al. The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J Immunol 1994; 153:5586–5592.

    PubMed  CAS  Google Scholar 

  4. Chomez P, De Backer O, Bertrand M, De Plaen E, Boon T, Lucas S. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res 2001; 61:5544–5551.

    PubMed  CAS  Google Scholar 

  5. Gaugler B, Van den Eynde B, van der Bruggen P, Romero P, Gaforio JJ, De Plaen E, et al. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med 1994; 179:921–930.

    Article  PubMed  CAS  Google Scholar 

  6. van der Bruggen P, Bastin J, Gajewski T, Coulie PG, Boel P, De Smet C, et al. A peptide encoded by human gene MAGE-3 and presented by HLA-A2 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE-3. Eur J Immunol 1994; 24:3038–3043.

    Article  PubMed  Google Scholar 

  7. Valmori D, Gileadi U, Servis C, Dunbar PR, Cerottini JC, Romero P, et al. Modulation of proteasomal activity required for the generation of a cytotoxic T lymphocyte-defined peptide derived from the tumor antigen MAGE-3. J Exp Med 1999; 189:895–906.

    Article  PubMed  CAS  Google Scholar 

  8. Chen YT, Scanlan MJ, Sahin U, Tureci O, Gure AO, Tsang S, et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci USA 1997; 94:1914–1918.

    Article  PubMed  CAS  Google Scholar 

  9. Jager E, Stockert E, Zidianakis Z, Chen YT, Karbach J, Jager D, et al. Humoral immune responses of cancer patients against “Cancer-Testis” antigen NY-ESO-1: correlation with clinical events. Int J Cancer 1999; 84:506–510.

    Article  PubMed  CAS  Google Scholar 

  10. Jager E, Chen YT, Drijfhout JW, Karbach J, Ringhoffer M, Jager D, et al. Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med 1998; 187:265–270.

    Article  PubMed  CAS  Google Scholar 

  11. Romero P, Dutoit V, Rubio-Godoy V, Lienard D, Speiser D, Guillaume P, et al. CD8+ T-cell response to NY-ESO-1: relative antigenicity and in vitro immunogenicity of natural and analogue sequences. Clin Cancer Res 2001; 7:766s-772s.

    Google Scholar 

  12. Wang RF, Johnston SL, Zeng G, Topalian SL, Schwartzentruber DJ, Rosenberg SA. A breast and melanoma-shared tumor antigen: T cell responses to antigenic peptides translated from different open reading frames. J Immunol 1998; 161:598–3606.

    Google Scholar 

  13. Rimoldi D, Rubio-Godoy V, Dutoit V, Lienard D, Salvi S, Guillaume P, et al. Efficient simultaneous presentation of NY-ESO-1/LAGE-1 primary and nonprimary open reading frame-derived CTL epitopes in melanoma. J Immunol 2000; 165:7253–7261.

    PubMed  CAS  Google Scholar 

  14. Boel P, Wildmann C, Sensi ML, Brasseur R, Renauld JC, Coulie P, et al. A new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity 1995; 2:167–175.

    Article  PubMed  CAS  Google Scholar 

  15. Van den Eynde B, Peeters O, De Backer O, Gaugler B, Lucas S, Boon T. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J Exp Med 1995; 182:689–698.

    Article  PubMed  Google Scholar 

  16. Coulie PG, Brichard V, Van Pel A, Wolfe! T, Schneider J, Traversari C, et al. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas [see comments]. J Exp Med 1994; 180:35–42.

    Article  PubMed  CAS  Google Scholar 

  17. Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Sakaguchi K Appella E, et al. Identification of a human melanoma antigen recognized by tumor infiltrating lymphocytes associated with in vivo tumor rejection. Proc Nat! Acad Sci USA 1994; 91:6458–6462.

    Article  CAS  Google Scholar 

  18. Harada M, Li YF, El-Gamil M, Rosenberg SA, Robbins PF. Use of an in vitro immunoselected tumor line to identify shared melanoma antigens recognized by HLA-A*0201-restricted T cells. Cancer Res 2001; 61:1089–1094.

    PubMed  CAS  Google Scholar 

  19. Kawakami Y, Dang N, Wang X, Tupesis J, Robbins PF, Wang RF, et al. Recognition of shared melanoma antigens in association with major HLA-A alleles by tumor infiltrating T lymphocytes from 123 patients with melanoma. J Immunother 2000; 23:17–27.

    Article  PubMed  CAS  Google Scholar 

  20. Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JB, et al. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2 restricted tumor infiltrating lymphocytes. J Exp Med 1994; 180:347–352.

    Article  PubMed  CAS  Google Scholar 

  21. Kawakami Y, Eliyahu S, Jennings C, Sakaguchi K, Kang X, Southwood S, et al. Recognition of multiple epitopes in the human melanoma antigen gp100 by tumor-infiltrating T lymphocytes associated with in vivo tumor regression. J Immunol 1995; 154:3961–3968.

    PubMed  CAS  Google Scholar 

  22. Cox AL, Skipper J, Chen Y, Henderson RA, Darrow TL, Shabanowitz J, et al. Identification of a peptide recognized by five melanoma-specific human cytotoxic T cell lines. Science 1994; 264:716–719.

    Article  PubMed  CAS  Google Scholar 

  23. Kawakami Y, Robbins PF, Wang X, Tupesis JP, Parkhurst MR, Kang X, et al. Identification of new melanoma epitopes on melanosomal proteins recognized by tumor infiltrating T lymphocytes restricted by HLA-Al, -A2 and -A3 alleles. J Immunol 1998;161: 6985–6992.

    PubMed  CAS  Google Scholar 

  24. Kawashima I, Tsai V, Southwood S, Takesako K, Celis E, Sette A. Identification of gp100-derived, melanoma-specific cytotoxic T-lymphocyte epitopes restricted by HLA-A3 supertype molecules by primary in vitro immunization with peptide-pulsed dendritic cells. Int J Cancer 1998; 78:518–524.

    Article  PubMed  CAS  Google Scholar 

  25. Robbins PF, El-Gamil M, Li YF, Fitzgerald EB, KawakamiY, Rosenberg, SA. The intronic region of an incompletely spliced gp100 gene transcript encodes an epitope recognized by melanoma-reactive tumor-infiltrating lymphocytes. J Immunol 1997; 159:303–308.

    PubMed  CAS  Google Scholar 

  26. Castelli C, Tarsini P, Mazzocchi A, Rini F, Rivoltini L, Ravagnani F, et al. Novel HLA-Cw8-restricted T cell epitopes derived from tyrosinase-related protein-2 and gp100 melanoma antigens. J Immunol 1999; 162:1739–1748.

    PubMed  CAS  Google Scholar 

  27. Wolfel T, Van Pel A, Brichard V, Schneider J, Seliger B, Meyer zum Buschenfelde KH. Two tyrosinase nonapeptides recognized on HLA-A2 melanomas by autologous cytolytic T lymphocytes. EurJ Immunol 1994; 24:759–764.

    Article  CAS  Google Scholar 

  28. Parkhurst MR, Fitzgerald EB, Southwood S, Sette A, Rosenberg SA, Kawakami Y. Identification of a shared HLA-A*0201-restricted T-cell epitope from the melanoma antigen tyrosinase-related protein 2 (TRP2). Cancer Res 1998; 58:4895–4901.

    PubMed  CAS  Google Scholar 

  29. Tsai V, Southwood S, Sidney J, Sakaguchi K, Kawakami Y, Appella E, et al. Identification of subdominant CTL epitopes of the GP100 melanoma-associated tumor antigen by primary in vitro immunization with peptide-pulsed dendritic cells. J Immunol 1997; 158:1796–1802.

    PubMed  CAS  Google Scholar 

  30. Riley, JP, Rosenberg SA, Parkhurst MR. Identification of a new shared HLA-A2.1 restricted epitope from the melanoma antigen tyrosinase. J Immunother 2001; 24:212–220.

    Article  CAS  Google Scholar 

  31. Salazar-Onfray F, Nakazawa T, Chhajlani V, Petersson M, Karre K, Masucci G, et al. Synthetic peptides derived from the melanocyte-stimulating hormone receptor MC1R can stimulate HLA-A2-restricted cytotoxic T lymphocytes that recognize naturally processed peptides on human melanoma cells. Cancer Res 1997; 57:4348–4355.

    PubMed  CAS  Google Scholar 

  32. Touloukian CE, Leitner WW, Robbins PF, Rosenberg SA, Restifo NP. Mining the melanosome for tumor vaccine targets: P. polypeptide is a novel tumor-associated antigen. Cancer Res 2001; 61:8100–8104.

    PubMed  CAS  Google Scholar 

  33. Touloukian CE, Leitner WW, Schnur RE, Robbins PF, Li Y, Southwood S, Sette A, et al. Normal tissue depresses while tumor tissue enhances human T cell responses in vivo to a novel self/tumor melanoma antigen, OA 1. J Immunol 2003; 170:1579–1585.

    PubMed  CAS  Google Scholar 

  34. Ikeda H, Lethe B, Lehmann F, van Baren N, Baurain JF, de Smet C, et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity 1997; 6:199–208.

    Article  PubMed  CAS  Google Scholar 

  35. Robbins PF, El-Gamil M, Li YF, Topalian SL, Rivoltini L, Sakaguchi K, et al. Cloning of a new gene encoding an antigen recognized by melanoma-specific HLA-A24 restricted tumor-infiltrating lymphocytes. J Immunol 1995; 154:5944–5950.

    PubMed  CAS  Google Scholar 

  36. Harada M, Li YF, El-Gamil M, Ohnmacht GA, Rosenberg SA, Robbins PF. Melanoma-reactive CD8+ T cells recognize a novel tumor antigen expressed in a wide variety of tumor types. J Immunother 2001; 24:323–333.

    Article  PubMed  CAS  Google Scholar 

  37. Mandruzzato S, Brasseur F, Andry G, Boon T, van der Bruggen P. A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma. J Exp Med 1997; 186:785–793.

    Article  PubMed  CAS  Google Scholar 

  38. Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, et al. pl6INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 1995; 269:1281–1284.

    Article  PubMed  CAS  Google Scholar 

  39. Robbins PF, El-Gamil M, Li YF, Kawakami Y, Loftus D, Appella, E, Rosenberg SA. A mutated bcatenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J Exp Med 1996; 183:1185–1192.

    Article  PubMed  CAS  Google Scholar 

  40. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Stabilization of beta-catenin by genetic defects in melanoma cell lines [see comments]. Science 1997; 275:1790–1792.

    Article  PubMed  CAS  Google Scholar 

  41. Ranade K, Hussussian CJ, Sikorski RS, Varmus HE, Goldstein AM, et al. Mutations associated with familial melanoma impair p16INK4 function. Nat Genet 1995; 10:114–116.

    Article  PubMed  CAS  Google Scholar 

  42. Chinnaiyan AM, Tepper CG, Seldin, MF, O’Rourke K, Kischkel FC, Hellbardt S, et al. FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. J Biol Chem 1996; 271:4961–4965.

    Article  PubMed  CAS  Google Scholar 

  43. Hsu H, Xiong J, Goeddel, DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 1995; 81:495–504.

    Article  PubMed  CAS  Google Scholar 

  44. Barker N, Morin PJ, Clevers H. The Yin-Yang of TCF/beta-catenin signaling. Adv Cancer Res 2000; 77:1–24.

    Article  PubMed  CAS  Google Scholar 

  45. Guilloux Y, Lucas S, Brichard VG, Van Pel A, Viret C, De Plaen E, et al. A peptide recognized by human cytolytic T lymphocytes on HLA-A2 melanomas is encoded by an intron sequence of the Nacetylglucosaminyltransferase V gene. J Exp Med 1996; 183:1173–1183.

    Article  PubMed  CAS  Google Scholar 

  46. Lupetti R, Pisarra P, Verrecchia A, Farina C, Nicolini G, Anichini A. Translation of a retained intron in tyrosinase-related protein (TRP) 2 mRNA generates a new cytotoxic T lymphocyte (CTL)-defined and shared human melanoma antigen not expressed in normal cells of the melanocytic lineage. J Exp Med 1998; 188:1005–1016.

    Article  PubMed  CAS  Google Scholar 

  47. Moreau-Aubry A, Le Guiner S, Labarriere N, Gesnel MC, Jotereau F, Breathnach R. A processed pseudogene codes for a new antigen recognized by a CD8(+) T cell clone on melanoma. J Exp Med 2000; 191:1617–1624.

    Article  PubMed  CAS  Google Scholar 

  48. Hanada K, Perry-Lalley DM, Ohnmacht GA, Bettinotti MP, Yang JC. Identification of fibroblast growth factor-5 as an overexpressed antigen in multiple human adenocarcinomas. Cancer Res 2001; 61:5511–5516.

    PubMed  CAS  Google Scholar 

  49. Wang RF, Wang X, Rosenberg SA. Identification of a novel major histocompatibility complex class II-restricted tumor antigen resulting from a chromosomal rearrangement recognized by CD4(+) T cells. J Exp Med 1999; 189:1659–1668.

    Article  PubMed  CAS  Google Scholar 

  50. Wang RF, Wang X, Atwood AC, Topalian SL, Rosenberg SA. Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor antigen. Science 1999; 284:1351–1354.

    Article  PubMed  CAS  Google Scholar 

  51. Pieper R, Christian RE, Gonzales MI, Nishimura MI, Gupta G, Settlage RE, et al. Biochemical identification of a mutated human melanoma antigen recognized by CD4(+) T cells. J Exp Med 1999; 189: 757–766.

    Article  PubMed  CAS  Google Scholar 

  52. Topalian SL, Gonzales MI, Parkhurst M, Li YF, Southwood S, Sette A, et al. Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes. J Exp Med 1996; 183:1965–1971.

    Article  PubMed  CAS  Google Scholar 

  53. Robbins PF, El-Gamil M, Li YF, Zeng G, Dudley M, Rosenberg SA. Multiple HLA class II-restricted melanocyte differentiation antigens are recognized by tumor-infiltrating lymphocytes from a patient with melanoma. J Immunol 2002; 169:6036–6047.

    PubMed  CAS  Google Scholar 

  54. Manici S, Sturniolo T, Imro MA, Hammer J, Sinigaglia F, Noppen C, et al. Melanoma cells present a MAGE-3 epitope to CD4(+) cytotoxic T cells in association with histocompatibility leukocyte antigen DR11 [see comments]. J Exp Med 1999; 189:871–876.

    Article  PubMed  CAS  Google Scholar 

  55. Chaux P, Vantomme V, Stroobant V, Thielemans K, Corthals J, Luiten R, et al. Identification of MAGE3 epitopes presented by HLA-DR molecules to CD4(+) T lymphocytes [see comments]. J Exp Med 1999; 189:767–778.

    Article  PubMed  CAS  Google Scholar 

  56. Schultz ES, Lethe B, Cambiaso CL, Van Snick J, Chaux P, Corthals J, et al. MAGE-A3 peptide presented by HLA-DP4 is recognized on tumor cells by CD4+ cytolytic T lymphocytes. Cancer Res 2000; 60:6272–6275.

    PubMed  CAS  Google Scholar 

  57. Chaux P, Lethe B, Van Snick J, Corthals J, Schultz ES, Cambiaso CL, et al. MAGE-1 peptide recognized on HLA-DR15 by CD4(+) T cells. Eur J Immunol 2001; 31:1910–1916.

    Article  PubMed  CAS  Google Scholar 

  58. Lapointe R, Royal RE, Reeves ME, Altomare I, Robbins PF, Hwu P. Retrovirally transduced human dendritic cells can generate T cells recognizing multiple MHC class I and class II epitopes from the melanoma antigen glycoprotein 100. J Immunol 2001; 167:4758–4764.

    PubMed  CAS  Google Scholar 

  59. Touloukian CE, Leitner WW, Robbins PF, Li YF, Kang X, Lapointe R, et al. Expression of a “self-” antigen by human tumor cells enhances tumor antigen-specific CD4(+) T-cell function. Cancer Res 2002; 62:5144–5147.

    PubMed  CAS  Google Scholar 

  60. Zeng G, Touloukian CE, Wang X, Restifo NP, Rosenberg SA, Wang RF. Identification of CD4+ T cell epitopes from NY-ESO-1 presented by HLA-DR molecules. J Immunol 2000; 165:1153–1159.

    PubMed  CAS  Google Scholar 

  61. Zarour HM, Storkus WJ, Brusic V, Williams E, Kirkwood JM. NY-ESO-1 encodes DRB1*0401–restricted epitopes recognized by melanoma-reactive CD4+ T cells. Cancer Res 2000; 60:4946–4952.

    PubMed  CAS  Google Scholar 

  62. Jager E, Jager D, Karbach J, Chen YT, Ritter G, Nagata Y, et al. Identification of NY-ESO-1 epitopes presented by human histocompatibility antigen (HLA)-DRB4*0101–0103 and recognized by CD4(+) T lymphocytes of patients with NY-ESO-1-expressing melanoma. J Exp Med 2000; 191:625–630.

    Article  PubMed  CAS  Google Scholar 

  63. Slager EH, Borghi M, Van Der Minne CE, Aarnoudse CA, Havenga MJ, Schrier PI, et al. CD4(+) Th2 cell recognition of HLA-DR-restricted epitopes derived from CAMEL: a tumor antigen translated in an alternative open reading frame. J Immunol 2003; 170:1490–1497.

    PubMed  CAS  Google Scholar 

  64. Zeng G, Wang X, Robbins PF, Rosenberg SA, Wang RF. CD4(+) T cell recognition of MHC class II-restricted epitopes from NY-ESO-1 presented by a prevalent HLA DP4 allele: association with NYESO-1 antibody production. Proc Natl Acad Sci USA 2001; 98:3964–3969.

    Article  PubMed  CAS  Google Scholar 

  65. Gjertson DW, Lee SH, Kawata J, Sutrisno R. HLA 1997. Los Angeles: UCLA Tissue Typing Laboratory, 1997: 174–427.

    Google Scholar 

  66. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 2000; 74:181–273.

    Article  PubMed  CAS  Google Scholar 

  67. Restifo NP, Marincola FM, Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA. Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst 1996; 88:100–108.

    Article  PubMed  CAS  Google Scholar 

  68. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298:850–854.

    Article  PubMed  CAS  Google Scholar 

  69. Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL, et al. Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 2001; 24:363–373.

    Article  PubMed  CAS  Google Scholar 

  70. Chiari R, Hames G, Stroobant V, Texier C, Maillere B, Boon T, Coulie PG. Identification of a tumorspecific shared antigen derived from an Eph receptor and presented to CD4 T cells on HLA class II molecules. Cancer Res 2000; 60:4855–4863.

    PubMed  CAS  Google Scholar 

Download references

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Humana Press Inc.

About this chapter

Cite this chapter

Robbins, P.F. (2004). Tumor Antigen Discovery With T Cells. In: Morse, M.A., Clay, T.M., Lyerly, H.K. (eds) Handbook of Cancer Vaccines. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-680-5_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-680-5_4

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4684-9818-9

  • Online ISBN: 978-1-59259-680-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics