Cancer Immunology, Immunotherapy

, Volume 45, Issue 1, pp 10–19

Carbohydrate vaccines that induce antibodies against cancer. 2. Previous experience and future plans

  • Philip O. Livingston
  • Govindaswami Ragupathi

In conclusion

The primary function of antibodies is the elimination of circulating viral or bacterial pathogens from the blood-stream, lymphatics and interstitial spaces, and so, once induced, antibodies should be ideally suited for eliminating tumor cells and micrometastases from these spaces as well. Natural or tumor-induced and vaccine-induced antibodies against human cancer-associated antigens have been correlated with an improved clinical outcome. In the mouse, passive administration of monoclonal antibodies against cell-surface antigens 1–4 days after tumor challenge, and active induction of antibodies with vaccines, has resulted in prolonged survival or complete protection from tumor growth. This is a setting similar to the adjuvant setting in humans. Carbohydrates are the most abundant antigens at the cell surface of cancer cells, where they play important roles in cell-cell interactions, proliferation and the metastatic process. They have been shown to be excellent targets for immune attack by antibodies against human cancers, especially in the adjuvant setting. Vaccines containing these carbohydrate antigens covalently attached to immunogenic carrier proteins, such as KLH, plus potent immunological adjuvants, such as QS-21, effectively induce antibodies against these antigens in patients, which can result in complement-mediated lysis of antigen-positive tumor cells. Phase III trials with KLH conjugate vaccines have been initiated in the adjuvant setting against two carbohydrate antigens, the ganglioside GM2 and the blood-group-related antigen sTn. As the immunogenicity of additional vaccines is confirmed in small pilot trials, trials with polyvalent vaccines against two to five different antigens tailored for particular cancer types are planned.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Zhang S, Cordon-Cardo C, Zhang HS, Reuter VE, Adluri S, Hamilton WB, Lloyd KO, Livingston PO (1997) Selection of carbohydrate tumor antigens as targets for immune attack using immunohistochemistry. I. Focus on gangliosides. Int J Cancer (in press)Google Scholar
  2. 2.
    Zhang S, Zhang HS, Cordon-Cardo C, Reuter VI, Lloyd KO, Livingston PO (1997) Selection of blood group-related tumor antigens as targets for immune attack using immunohistochemistry: II. Blood group-related antigens. Int J Cancer (in press)Google Scholar
  3. 3.
    Livingston PO, Sznol M (1997) Vaccine therapy for melanoma. In: Balch CM (ed) Cutaneous melanoma, 3rd edm. Lippincott, Philadelphia, (in press)Google Scholar
  4. 4.
    Livingston PO, Wong GYC, Adluri S, Tao Y, Padavan M, Parente R, Hanlon C, Helling F, Ritter G, Oettgen HE, Old LJ (1994) Improved survival in AJCC stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol 13:1036–1044Google Scholar
  5. 5.
    Tai T, Cahan LD, Tsuchida T, Saxton RE, Irie RF, Morton DL (1985) Immunogenicity of melanoma-associated gangliosides in cancer patients. Int J Cancer 35:607PubMedCrossRefGoogle Scholar
  6. 6.
    Kawakami Y, Eliyahu S, Jennings C, Sakaguchi K, Kang X, Southwood S, Robbins P, Sette A, Appella E, Rosenberg S (1995) Recognition of multiple epitopes in the human melanoma antigen gp 100 by tumor-infiltrating T lymphocytes associated with in viva tumor regression. J Immunol 154:3961–3968PubMedGoogle Scholar
  7. 7.
    Houghton AN, Mintzer D, Cordon-Cardo C, Welt S, Fliegel B, Vadhan S, Carswell E, Melamed MR, Oettgen HF, Old LJ (1985) Mouse monoclonal antibody IgG3 antibody detecting GD3 up, ganglioside: a phase I trial in patients with malignant melanoma. Proc Natl Acad Sci USA 82:1242–1246PubMedCrossRefGoogle Scholar
  8. 8.
    Dippold WG, Bernhard H, Peter Dienes H, Meyer zum Buschenfelde KH (1988) Treatment of patients with malignant melanoma by monoclonal ganglioside antibodies. Eur J Cancer Clin Oncol 24:S65-S67Google Scholar
  9. 9.
    Raymond J, Kirkwood J, Vlock D, Rabkin M, Day R, Whiteside T, Herberman R, Mascari R, Simon B (1988) A phase IB trial of murine monoclonal antibody R24 (anti-GD3) in metastatic melanoma (abstract). Proc Am Soc Clin Oncol 7:A958Google Scholar
  10. 10.
    Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber IS, Parkinson DR, Seipp CA, Einhorn JH, White DE (1994) Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin-2 [see comments]. J Natl Cancer Inst 86:1159–1166PubMedCrossRefGoogle Scholar
  11. 11.
    Schwartzentruber DJ, Horn SS, Dadmarz R, White DE, Yannelli JR, Steinberg SM, Rosenberg SA, Topalian SL (1994) In vitro predictors of therapeutic response in melanoma patients receiving tumor-infiltrating lymphocytes and interleukin-2. J Clin Oncol 12: 1475–1483PubMedGoogle Scholar
  12. 12.
    Livingston PO, Ritter G, Srivastava P, Padavan M, Calves MJ, Oettgen HE, Old LJ (1989) Characterization of IgG and IgM antibodies induced in melanoma patients by immunization with purified GM2 ganglioside. Cancer Res 49:7045–7050PubMedGoogle Scholar
  13. 13.
    Longenecker BM, Reddish M, Miles D, MacLean GD (1993) Synthetic tumor-associated sialyl-Tn antigen as an immunotherapeutic cancer vaccine. Vaccine Res 2:151–161Google Scholar
  14. 14.
    Mukherji B, Chakraborty NG, Yamasaki S, Okino T, Yamase H, Sporn JR, Kurtzman SK, Ergin MT, Ozols J, Meehan J (1995) Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc Nat Acad Sci USA 92: 8078–8082PubMedCrossRefGoogle Scholar
  15. 15.
    Hoon DS, Yuzuki D, Hayashida M, Morton DL (1995) Melanoma patients immunized with melanoma cell vaccine induce antibody responses to recombinant MAGE-1 antigen. J Immunol 154: 730–737PubMedGoogle Scholar
  16. 16.
    Livingston PO (1997) The case for melanoma vaccines that induce antibodies. In: Kirkwood JM (ed) Molecular diagnosis, prevention and treatment of melanoma. Marcel Dekker (in press)Google Scholar
  17. 17.
    Krementz ET, Samuels MS, Wallace JH et al (1971) Clinical experiences in immunotherapy of cancer. Surg Gynecol Obstet 33:209Google Scholar
  18. 18.
    Berd D, Murphy G, Maguire HC Jr, Mastrangelo MJ (1990) Treatment of metastatic melanoma with an autologous tumor-cell vaccine: clinical and immunologic results in 64 patients. J Clin Oncol 8:1858–1867PubMedGoogle Scholar
  19. 19.
    Mitchell MS, Harel W, Kempf RA, Hu E, Kan-Mitchell J, Boswell WD, Dean G, Stevenson L (1990) Active-specific immunotherapy for melanoma. J Clin Oncol 8:856–869PubMedGoogle Scholar
  20. 20.
    Livingston PO, Oettgen HF, Old LJ (1982) Specific active immunotherapy in cancer therapy. In: Mihich E (ed) Immunological aspects of cancer therapeutics. Wiley, New York, pp 363–404Google Scholar
  21. 21.
    Livingston PO (1991) Active specific immunotherapy in the treatment of cancer. In: Ottegen HF (ed) Immunology and allergy clinics of North America. Human cancer immunology. II, vol 11. Saunders, London, pp 402–423Google Scholar
  22. 22.
    Morton DL, Foshag LJ, Hoon DS, Nizze JA, Famatiga E, Wanek LA, Chang C, Irie RF, Gupta RK, Elashioff R (1993) Polyvalent melanoma vaccine improves survival of patients with metastatic melanoma. Ann NY Acad Sci 690:120–134PubMedCrossRefGoogle Scholar
  23. 23.
    Laucius JF, Bodurtha AJ, Mastrangelo MJ, Bellet RE (1977) A phase II study of autologous irradiated tumor cells plus BCG in patients with metastatic melanoma. Cancer 40:2091–2093PubMedCrossRefGoogle Scholar
  24. 24.
    Livingston PO, Zhang S, Lloyd K (1997) Carbohydrate vaccines that induce antibodies against cancer. Part 1. Rationale. Cancer Immunol Immunother 45:1–9PubMedCrossRefGoogle Scholar
  25. 25.
    Norrby E, Enders-Ruckle G, Ter Meulen V (1975) Differences in the appearance of antibodies to structural components of measles virus after immunization with inactivated and live virus. J Infect Dis 132:262PubMedGoogle Scholar
  26. 26.
    Oehen S, Hengartner H, Zinkernagel RM (1991) Vaccination for disease. Science 251:195–198PubMedCrossRefGoogle Scholar
  27. 27.
    Weigle WO (1977) Autoimmunity: genetic, immunologic, virologic, and clinical aspects. In: Talal (ed) Academic Press, New York London, pp 141–170Google Scholar
  28. 28.
    Stuart JM, Cremer MA, Townes AS, et al (1982) Type II collagen-induced arthritis in rats. J Exp Med 155:1–10PubMedCrossRefGoogle Scholar
  29. 29.
    Paterson PY (1983) LT/EAE and MS quest. Cell Immunol 82: 55–65PubMedCrossRefGoogle Scholar
  30. 30.
    Allison AC (1977) Autoimmune diseases: concepts of pathogenisis and control. In: Talal N (ed) Autoimmunity: genetic, immunologic, virologie, and clinical aspects. Academic Press, New York London, pp 91–139Google Scholar
  31. 31.
    Rose NR (1981) Autoimmune disease. Sci Am 244:80PubMedGoogle Scholar
  32. 32.
    Lin R-H, Mamula MJ, Hardin JA, Janeway CA Jr (1991) Induction of autoreactive B cells allows priming of autoreactive T cells. J Exp Med 173:1433–1439PubMedCrossRefGoogle Scholar
  33. 33.
    Ritter G, Boosfeld E, Markstein E, Yu RK, Ren S, Oettgen HF, Old LJ, Livingston PO (1990) Biochemical and serological characteristics of natural 9-O-acetyl GD3 from human melanoma and bovine buttermild and chemically O-acetylated GD3. Cancer Res 50:1403–1410PubMedGoogle Scholar
  34. 34.
    Ritter G, Boosfeld E, Calves MJ, Oettgen HF, Old LJ, Livingston PO (1990) Antibody response after immunization with gangliosides GD3, GD3 lactones, GD3 amide and GD3 gangliosidol in the mouse. GD3 lactone I induces antibodies reactive with human melanoma. Immunobiology 182:32–43PubMedGoogle Scholar
  35. 35.
    Helling F, Shang Y, Calves M, Oettgen HF, Livingston PO (1994) Increased immunogenicity of GD3 conjugate vaccines: comparison of various carrier proteins and selection of GD3-KLH for further testing. Cancer Res 54:197–203PubMedGoogle Scholar
  36. 36.
    Kensil CR, Patel U, Lennick M, Marciani D (1991) Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex. J Immunol 146:431–437PubMedGoogle Scholar
  37. 37.
    Livingston PO, Koganty R, Longenecker BM, Lloyd KO, Calves M (1992) Studies on the immunogenicity of synthetic and natural Thomsen-Friedenreich (TF) antigens in mice: augmentation of the response by Quil A and SAF-m adjuvants and analysis of the specificity of the responses. Vaccines Res 1:99–109Google Scholar
  38. 38.
    Toyokuni T, Dean B, Cai S, Boivin D, Hakomori S, Singhai AK (1994) Synthetic vaccines: synthesis of a dimeric Tn antigen-lipopeptide conjugate that elicits immune responses against Tn-expressing glycoproteins. J Am Chem Soc 116:395–396CrossRefGoogle Scholar
  39. 39.
    Toyokuni T, Singhai AK (1995) Recent progress in synthetic vaccines based on tumor-associated carbohydrate antigens. Chem Soc Rev 24:231–242CrossRefGoogle Scholar
  40. 40.
    Zhang S, Walberg LA, Ogata S, Itzkowitz SH, Koganty RR, Reddish M, Gandhi SS, Longenecker BM, Lloyd KO, Livingston PO (1995) Immune sera and monoclonal antibodies define two configurations for the sialyl Tn tumor antigen. Cancer Res 55:3364–3368PubMedGoogle Scholar
  41. 41.
    Ragupathi G, Park TK, Zhang S, Kim IJ, Graeber K, Adluri S, Lloyd KO, Danishefsky SJ, Livingston PO (1997) Immunization of mice with the synthetic hexasaccaride GloboH results in antibodies against human cancer cells. Angew Chem 36:125–128CrossRefGoogle Scholar
  42. 42.
    Kudryashov V, Ragupathi G, Kim LJ, Livingston PO, Danishefsky SJ, Lloyd KO (1997) Immunogenicity of synthetic Lewis Y oligosaccharide-protein conjugates in mice: towards the design of anti-cancer vaccines. Cancer Immunol Immunother (in press)Google Scholar
  43. 43.
    Singhal AK, Fohn M, Hakomori S (1991) Induction of Tn (α-N-acetylgalactosamine-O-serine/ threoninine) antigen-mediated cellular immune response for active immunotherapy in mice. Cancer Res 51:1406–1411PubMedGoogle Scholar
  44. 44.
    Fung PYS, Madej M, Koganti R, Longenecker BM (1990) Active specific immunotherapy of a murine mammary adenocarcinoma using a synthetic tumor-associated glycoconjugate. Cancer Res 50:4308–4314PubMedGoogle Scholar
  45. 45.
    Livingston PO (1995) Approaches to augmenting the immunogenicity of melanoma gangliosides: from whole melanoma cells to ganglioside-KLH conjugate vaccines. Immunol Rev 145:145–166CrossRefGoogle Scholar
  46. 46.
    Livingston PO, Natoli EJ Jr, Jones Calves M, Stocken E, Oettgen HF, Old LJ (1987) Vaccines containing purified GM2 ganglioside elicit GM2 antibodies in melanoma patients. Pro Natl Acad Sci USA 84:2911–2915CrossRefGoogle Scholar
  47. 47.
    Hofstad T, Skaug N, Sveen K (1993) Stimulation of B lymphocytes by lipopolysaccharides from anaerobic bacteria. Clin Infect Dis 16[Suppl 4]:S200–205PubMedGoogle Scholar
  48. 48.
    Livingston PO, Zhang S, Walberg L, Ragupathi G, Helling F, Fleischer M (1997) Tumor cell reactivity medicated by IgM antibodies in sera from melanoma patients vaccinated with GM2-KLH is increased by IgG antibodies. Cancer Immunol Immunotherapy 43:324–330CrossRefGoogle Scholar
  49. 49.
    Livingston PO, Adluri S, Helling F, Yao TJ, Kensil CR, Newman MJ, Marciani D (1994) Phase I trial of immunological adjuvant QS-21 with a GM2 ganglioside-KLH conjugate vaccine in patients with malignant melanoma. Vaccine 12:1275–1280PubMedCrossRefGoogle Scholar
  50. 50.
    Ritter G, Boosfeld E, Adluri R, Calves M, Oettgen HF, Old LJ, Livingston PO (1991) Antibodies response to immunization with ganglioside GD3 and GD3 congeners (lactones, amide and gangliosidol) in patients with malignant melanoma. Int J Cancer 48:379–385PubMedCrossRefGoogle Scholar
  51. 51.
    Ritter G, Boosfeld E, Adluri R, Calves M, Ren S, Ye RK, Oettgen HF, Old LJ, Livingston PO (1995) Analysis of the antibody response to immunisation with purified O-acetyl GD3 gangliosides in patients with malignant melanoma. Int J Cancer 62:1–5CrossRefGoogle Scholar
  52. 52.
    Springer GF, Desai PR, Tegtmeyer H. Spencer BD, Scanion EF (1993) Pancarcinoma T/Tn antigen detects human carcinoma long before biopsy does and its vaccine prevents breast carcinoma recurrence. Ann NY Acad Sci 690:355–357PubMedCrossRefGoogle Scholar
  53. 53.
    O’Boyle KP, Zamore R, Adluri S, Cohen A, Kemeny N, Welt S, Lloyd KO, Oettgen HF, Old LJ, Livingston PO (1992) Immunization of colorectal cancer patients with modified ovine submaxillary gland mucin and adjuvants induces IgM and IgG antibodies to sialylated Tn. Cancer Res 52:5663–5667PubMedGoogle Scholar
  54. 54.
    McLean GD, Bowen-yacyshyn MB, Samuel J, Meikle A, Stuart G, Nation J, Poppema S, Jerry M, Koganty R, Wong T, Longenecker BM (1992) Active immunization of human ovarian cancer patients against a common carcinoma (Thomsen-Friedenreich) determinant using a synthetic carbohydrate antigen. J Immunother 11:292–301Google Scholar
  55. 55.
    Adluri S, Helling F, Calves MJ, Lloyd KO, Livingston PO (1995) Immunogenicity of synthetic TF and sTn-KLH conjugates in colorectal carcinoma patients. Cancer Immunol Immunother 41:185–192PubMedCrossRefGoogle Scholar
  56. 56.
    MacLean GD, Miles DW, Rubens RD, Reddish MA, Longenecker BM (1996) Enhancing the effect of Theratope STn-KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenous cyclophosphamide. J Immunotherapy 19:309–316CrossRefGoogle Scholar
  57. 57.
    Bystryn JC, Oratz R, Roses D, Harris M, Henn M, Lew R (1992) Relationship between immune response to melanoma vaccine immunization and clinical outcome in stage II malignant melanoma. Cancer 69:1157–1164PubMedGoogle Scholar
  58. 58.
    Mittelman A, Chen GZJ, Wong GU, Liu C, Hirai S, Ferrone S (1995) Human high molecular weight-melanoma associated antigen mimicry by mouse antiidiotypic monoclonal antibody MD2-23: modulation of the immunogenicity in patients with malignant melanoma. Clin Cancer Res 1:705–713PubMedGoogle Scholar
  59. 59.
    Barth A, Hoon DS, Foshag LJ, Nizze JA, Famatiga E, Okun E, Morton DL (1994) Polyvalent melanoma cell vaccine induces delayed-type hypersensitivity and in vitro cellular immune response. Cancer Res 54:3342–3345PubMedGoogle Scholar
  60. 60.
    Livingston PO, Kaelin E, Pinsky CM, Oettgen HF, Old LJ (1985) IV. Serologic response in stage II melanoma patients receiving allogeneic melanoma cell vaccines. Cancer 56:2194–2200PubMedCrossRefGoogle Scholar
  61. 61.
    Jones PC, Sze LL, Liu PY, Morton DL, Irie RF (1981) Prolonged survival for melanoma patients with elevated antibody to oncofetal antigen. J Natl Cancer Inst 66:249–254PubMedGoogle Scholar
  62. 62.
    MacLean GD, Reddish MA, Koganly RR, Longenecker BM (1996) Antibodies against mucin-associated sialyl-Tn epitopes correlate with survival of metastatic adenocarcinoma patients undergoing active specific immunotherapy with synthetic STn vaccine. J Immunother 19:59–68CrossRefGoogle Scholar
  63. 63.
    Springer OF (1995) T and Tn pancarcinoma markers: autoantigenic adhesion molecules in pathogenesis, prebiopsy carcinoma-detection, and long-term breast carcinoma immunotherapy. Cri Rev Oncog 6:57–85Google Scholar
  64. 64.
    Kundu SK, Marcus DM (1978) Production of antibodies to GD3. Fed Proc 37:1766Google Scholar
  65. 65.
    Gray GR (1978) Antibodies to carbohydrates: preparation of antigens by coupling carbohydrates to proteins by reductive amination with cyanoborohydride. Methods Enzymol 50:155–160PubMedCrossRefGoogle Scholar
  66. 66.
    Helling F, Zhang A, Shang A, Adluri S, Calves M, Koganty R, Longenecker BM, Oettgen HF, Livingston PO (1995) GM2-KLH conjugate vaccine: Increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res 55:2783–2788PubMedGoogle Scholar
  67. 67.
    Serreze DV, Chapman HD, Varnum DS, Hanson MS, Reifsnyder PC, Richard SD, Fleming SA, Leiter EH, Shultz LD (1996) B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Igμnull mice. J Exp Med 184:2049–2053PubMedCrossRefGoogle Scholar
  68. 68.
    Sopori ML, Donaldson LA, Savage SM (1990) T lymphocyte heterogeneity in the rat. III. Autoreactive T cells are activated by B cells. Cell Immun 128:427437CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • Philip O. Livingston
    • 1
  • Govindaswami Ragupathi
    • 1
  1. 1.Department of MedicineMemorial Sloan-Kettering Cancer CenterNew York CityUSA

Personalised recommendations