TF Tn and sTn Vaccines

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Patients with various epithelial cancers have been immunized with unclustered TF-KLH and sTn-KLH vaccines plus various adjuvants (84,85). High-titer IgM and IgG antibodies against TF and sTn antigens resulted. In our hands the majority of the reactivity was against antigenic epitopes present in the vaccine that were not present on naturally expressed mucins (porcine or ovine submaxillary mucins [PSM or OSM]) or tumor cells (84,86). Based on previous studies with Tn antigen (87), Kurosaka and Nakada et al. hypothesized that MLS102, a monoclonal antibody against sTn, might preferentially recognize clusters ((c)) of sTn (88). Studies with monoclonal antibody B72.3 and with sera raised against TF-KLH and sTn-KLH conjugate vaccines in mice and in patients resulted in the same conclusion (41,84,86). The availability of synthetic TF, Tn, and sTn clusters consisting of three epitopes covalently linked to three consecutive serines or threonines has permitted proof of this hypothesis. In both direct tests and inhibition assays, B72.3 recognized sTn clusters exclusively, and sera from mice immunized with sTn (c)-KLH reacted strongly with both natural mucins and tumor cells expressing sTn (41). Based on this background, we initiated trials with the TF(c)-KLH, Tn(c)-KLH, and sTn(c)-KLH conjugate vaccines in patients with breast cancer. Antibodies of relevant high titer and specificity, including against OSM or PSM and cancer cells expressing TF, Tn, or sTn, were induced for the first time in our experience (Table 3). Based on these results, we plan to include clustered Tn, sTn, and TF in the polyvalent vaccines against epithelial cancers.

Several trials with TF, Tn, and sTn vaccines have been reported from other centers, and a large multicenter phase III trial with an sTn vaccine has been completed. George Springer's pioneering trials in breast cancer patients with vaccines containing TF and Tn purified from natural sources and mixed with typhoid vaccine (as adjuvant) began in the mid-1970s (34,89,90). DTH and IgM responses against the immunizing antigens and prolonged survival compared to historical controls were reported. MacLean immunized 10 ovarian cancer patients with synthetic TF conjugated to KLH plus immunological adjuvant Detox (monophosphoryl Lipid A plus BCG cell-wall skeletons) and described augmentation of IgG and IgM antibodies against synthetic TF in 9 of 10 patients (85). Lower levels of antibody reactivity against TF from natural sources were detected in some of these cases. MacLean has also immunized patients with breast and other adenocarcinomas with sTn-KLH plus Detox (13,51,91). Induction of IgM and IgG antibodies against synthetic and natural sources of sTn was seen in essentially all patients and this response was further increased by pretreatment of patients with a low dose of cyclophosphamide. Reactivity of these sera with natural mucins and tumor cells despite the use of an unclustered sTn vaccine is probably explained by the fourfold higher sTn/KLH epitope ratio achieved in the MacLean vaccine compared to our previous unclustered vaccine. Survival appeared to be improved overall compared to historical controls and patients who responded with high antibody titers survived longer than those with lower titers. Reactivity with breast cancer cells, including CDC, was described. This is the basis for the completed multicenter phase III randomized trial of the sTn-KLH plus Detox vaccine vs KLH alone plus Detox in breast cancer patients with stable disease or clinical response to chemotherapy. Although the sponsor's website reports this study did not reach its primary endpoint, subgroup analysis is being performed.

3.5. Polysialic Acid Vaccines

Initial attempts at preparing a vaccine against polysialic acid for use in military recruits who are at risk of group B meningococcus infection were unsuccessful. We also have completed analysis of a clinical trial with polysialic acid conjugated to KLH plus QS-21 and found that no antibody response could be induced. Consequently, we tested a second polysialic acid vaccine that had been modified (N-propionylated) to increase its immu-nogenicity in collaboration with Dr. Harold Jennings, who pioneered the use of N-propionylation for this purpose (92). This induced an antibody response against unmodified polysialic acid in five of six patients immunized (see Fig. 3). These vaccine-induced antibodies also reacted with SCLC cells (and were cytotoxic for antigen-positive bacteria). This N-propionylated polysialic acid vaccine is suitable for inclusion in our polyvalent vaccine against SCLC and possibly for trials in students and military recruits for prevention of group B meningococcus infections.

4. effector mechanisms of antibodies against cell-surface antigens

Immunization against the carbohydrate components generally results exclusively in an antibody response (see 15-17 for dissenting views), primarily an IgM antibody response. These IgM antibodies are known to induce complement activation resulting in inflammation, and phagocytosis of tumor cells by the reticuloendothelial system (opsonization) and CDC (reviewed in 1). IgG antibody responses can also induce complement activation (regarding IgG depending on the subclass, IgG1 and IgG3 being optimal in humans), and these same effector mechanisms. IgG antibodies of these subclasses are also known to induce ADCC. Serological analysis of the series of clinical trials described above has suggested that the six vaccines containing different glycolipids induced antibodies mediating CDC whereas the four vaccines containing carbohydrate or peptide epitopes carried by mucin molecules induced antibodies that were not capable of mediating CDC. To determine whether this dichotomy was a result of the properties of the induced antibodies (i.e., class and effector functions), the different target cells used, or the nature of the target antigens, we compared the cell-surface reactivity (assayed by FACS), complement-fixing ability (using the immune adherence [IA] assay), and the CDC activity of a panel of monoclonal antibodies and immune sera from these trials on the same two tumor cell lines. Antibodies against glycolipids GM2, globo H and Ley, protein KSA, and mucin antigens Tn, sTn, TF, and MUC1 all reacted with these antigens expressed on tumor cells and all fixed complement. CDC, however, was mediated by antibodies against the glycolipids and a globular protein (KSA), but not by antibodies against the mucin antigens.

It must be emphasized that although we showed that mucins are poor targets for complement-mediated lysis of tumor cells, studies have shown that induction of antibodies against either glycolipid or mucin antigens results in protection from tumor recurrence in several different preclinical mouse models (reviewed in refs. 8 and 9). Also, antibodies against either glycolipid or mucin epitopes correlate with a more favorable prognosis in patients (11-13,90). It does not appear that the inability of antibodies against mucin antigens to induce complement-mediated lysis is necessarily detrimental to the antitumor response. Consequently, complement-mediated inflammation, opsonization, and ADCC but not CDC are likely mechanisms for the prolonged survival seen in the preclinical experiments targeting mucin antigens and suggested in the clinical trials with passively administered and actively induced antibodies against mucin antigens. Regarding bacterial infections, this is supported by the severe consequences of hereditary deficiency states involving either the classical or alternate complement pathways and the comparatively trivial consequences to deficiencies of the complement membrane attack complex (93).

5. summary

The majority of even cancer patients who will eventually die of their cancer can initially be rendered free of detectable disease by surgery and/or chemotherapy. Adjuvant chemotherapy or radiation therapy at this point are generally only minimally beneficial, so there is real need for additional methods of eliminating residual circulating cancer cells and micrometastases. This is the ideal setting for treatment with a cancer vaccine. The immune response induced is critically dependent on both vaccine design and awareness of the antigenic epitope. For antibody induction there is one best vaccine design, conjugation of the antigen to an immunogenic protein such as KLH and the use of a potent adjuvant such as the saponins QS-21 and GPI-0100. This approach alone induced strong antibody responses against the glycolipids GM2, fucosyl GM1 and globo H, and cancer cells expressing these glycolipids. Other carbohydrate antigens require additional modifications to augment relevant immunogenicity. GD2 and GD3 lactones and N-propionylated polysialic acid were significantly more effective at inducing antibodies against the unmodified antigens and tumor cells expressing these antigens. Tn, sTn, and TF trimers (clusters) were significantly more effective than the monomers at inducing antibodies reactive with the cancer-cell surface.

Antibodies are ideally suited for eradicating pathogens from the bloodstream and from early tissue invasion. Passively administered and vaccine-induced antibodies have accomplished this, eliminating circulating tumor cells and systemic or intraperitoneal micrometastases in a variety of preclinical models, so antibody-inducing vaccines offer real promise in the adjuvant setting. Polyvalent vaccines will probably be required because of tumor cell heterogeneity, heterogeneity of the human immune response, and the correlation between overall antibody titer against tumor cells and antibody effector mechanisms. Over the next several years, phase II clinical trials designed to determine the clinical impact of polyvalent conjugate vaccines will be initiated in the adjuvant setting in patients with SCLC and several epithelial cancers.

references

1. Livingston PO. Augmenting the immunogenicity of carbohydrate antigens. In: Livingston PO, ed.

Cancer vaccines, seminars in cancer biology. 1995; 6:357-366.

2. Lloyd KO. Molecular characteristic of tumor antigens. Immunol Allergy Clinics No Am 1990; 10:765-779.

3. Hakomori SI. Tumor-associated carbohydrate antigens. Annu Rev Immunol 1984; 2:103-126.

4. Feizi T. Demonstration by monoclonal antibodies that carbohydrate structures of glycoproteins and glycolipids are onco-developmental antigens. Nature 1985; 314:53-57.

5. Ghossein R, Scher H, Gerald W, Kelly WK, Curley T, Amsterdam A, Zhang Z-F, Rosai J. Detection of circulating tumor cells in patients with localized and metastatic prostatic carcinoma: clinical implications. J Clin Oncol 1995; 13:1195-1200.

6. Brossart P, Keilholz U, Willhauck M, Scheibenbogen C, Möhler T, Hunstein W. Hematogenous spread of malignant melanoma cells in different stages of disease. J Investig Dermatol 1993; 101:887-889.

7. Hoon DSB, Wang Y, Dale PS, Conrad AJ, Schmid P, Garrison D, Kuo C, Foshag JJ, Nizze AJ, Morton DL. Detection of occult melanoma cells in blood with a multiple-marker polymerase chain reaction assay. J Clin Oncol 1995; 13:2109-2116.

8. Livingston PO. The case for melanoma vaccines that induce antibodies. In: Kirkwood JM, ed. Molecular diagnosis prevention and treatment of melanoma. New York: Marcel Dekker, 1998:139-157.

9. Zhang H, Zhang S, Cheung NK, Ragupathi G, Livingston PO. Antibodies can eradicate cancer micrometastases. Cancer Res 1998; 58:2844-2849.

10. Jones PC, Sze LL, Liu PY, Morton DL, Irie RF. Prolonged survival for melanoma patients with elevated IgM antibody to oncofetal antigen. J Natl Cancer Inst 1981; 66:249-254.

11. Livingston PO, Ritter G, Srivastava P. Padavan M, Calves MJ, Oettgen HF, Old LJ. Characterization of IgG and IgM antibodies induced in melanoma patients by immunization with purified GM2 ganglioside. Cancer Res 1989; 49:7045-7050.

12. Livingston PO, Wong GYC, Adluri S, Tao Y, Padavan M, Parente R, Hanlon C, Helling F, Ritter G, Oettgen HF, Old LJ. Improved survival in AJCC stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol 1994; 12:1036-1044.

13. MacLean GD, Reddish MA, Koganty RR, Longenecker BM. Antibodies against mucin-associated sialyl-Tn epitopes correlate with survival of metastatic adenocarcinoma patients undergoing active specific immunotherapy with synthetic STn vaccine. J Immunother 1996; 19:59-68.

14. Zhang S, Helling F, Lloyd KO, Livingston PO. Increased tumor cell reactivity and complement dependent cytotoxicity with mixtures of monoclonal antibodies against different gangliosides. Cancer Immunol Immunother 1995; 40:88-94.

15. Fung PYS, Madej M, Koganty RR, Longenecker BM. Active specific immunotherapy of a murine mammary adenocarcinoma using a synthetic tumor-associated glycoconjugate. Cancer Res 1990; 50:4308-4314.

16. Singhal A, Fohn M, Hakomori S-I. Induction of a-N-acetylgalactosamine-O-serine/threonine (Tn) antigen-mediated cellular immune response for active immunotherapy in mice. Cancer Res 1991; 51: 1406-1411.

17. Zhao X-J, Cheung N-K. GD2 Oligosaccharide: target for cytotoxic T lymphocytes. J Exp Med 1995; 182:67-74.

18. Zhang S, Cordon-Cardo C, Zhang HS, Reuter VE, Adluri S, Hamilton WB, Lloyd KO, Livingston PO. Selection of carbohydrate tumor antigens as targets for immune attack using immunohistochemistry. I. Focus on gangliosides. Int J Cancer 1997; 73:42-49.

19. Zhang S, Zhang HS, Cordon-Cardo C, Reuter VE, Singhal AK, Lloyd KO, Livingston PO. Selection of tumor antigens as targets for immune attack using immunohistochemistry. II. Blood group-related antigens. Int J Cancer 1997; 73:50-56.

20. Zhang S, Zhang HS, Cordon-Cardo C, Ragupathi G, Livingston PO. Selection of tumor antigens as targets for immune attack using immunohistochemistry: III protein antigens. Clin Cancer Res 1998; 4:2669-2676.

21. Zhang S, Zhang HS, Reuter VE, Lloyd KO, Scher HI, Livingston PO. Expression of potential target antigens for immunotherapy on primary and metastatic prostate cancers. Clin Cancer Res 1998; 4:295-302.

22. Nishinaka Y, Ravindranath MH, Irie RF. Development of a human monoclonal antibody to ganglioside GM2 with potential for cancer treatment. Cancer Res 1996; 56:5666-5671.

23. Nakamura K, Koike M, Shitara K, Kuwana Y, Kiuragi K, Igarashi S, Hasegawa M, Hanai N. Chimeric anti-ganglioside GM2 antibody with antitumor activity. Cancer Res 1994; 54:1511-1516.

24. Hellström I, Garrigues HJ, Garrigues U, Hellström KE. Highly tumor-reactive, internalizing, mouse monoclonal antibodies to Ley-related cell surface antigens. Cancer Res 1990; 50:2183-2190.

25. Canevari S, Fossati G, Balsari A, Sonnino S, Colnaghi MI. Immunochemical analysis of the determinant recognized by a monoclonal antibody (MBr1) which specifically binds to human mammary epithelial cells. Cancer Res 1983; 43:1301-1305.

26. Menard S, Tagliabue E, Canevari S, Fossati G, Colnaghi MI. Generation of monoclonal antibodies reacting with normal and cancer cells of human breast. Cancer Res 1983; 43:1295-1300.

27. Perrone F, Menard S, Canevari S, Claabrese M, Boracchi P, Bufalino R, Testori S, Baldini M, Colnaghi MI. Prognostic significance of the CaMBr1 antigen on breast carcinoma: relevance of the type of recognized glycoconjugate. Eur J Cancer 1993; 29A:2113-2117.

28. Colnaghi MI, Menard S, Da Dalt JG, Agresti R, Cattoretti G, Andreola S, Di Fronzo G, Del Vecchio M, Verderio L, Cascinelli N, Rilke F. A multiparametric study by monoclonal antibodies in breast cancer. In: Ceriani RL, ed. Immunological approaches to the diagnosis and therapy of breast cancer. New York: Plenum, 1987:21-32.

29. Trail PA, Willner SJ, Lasch AJ, Henderson S, Hofstead AM, Casazza AM, Firestone RA, Hellstrom I, Hellstrom KE. Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science 1993; 261:212-215.

30. Burchell J, Taylor-Papadimitriou J, Boshell M, Gendler S, Duhig T. A short sequence, within the amino acid tandem repeat of a cancer-associated mucin, contains immunodominant epitopes. Int J Cancer 1989; 44:691-696.

31. Gendler SJ, Spicer AP, Lalani E-N, Duhig T, Peat N, Burchell J, Pemberton L, Boshell M, Taylor-Papadimitriou J. Structure and biology of a carcinoma-associated mucin, MUC1. Am Rev Respir Dis 1991; 144:S42-S47.

32. Perez L, Hayes DF, Maimonis P, Abe M, O'Hara C, Kufe DW. Tumor selective reactivity of a monoclonal antibody prepared against a recombinant peptide derived from the DF3 human breast carcinoma-associated antigen. Cancer Res 1992; 52:2563-2568.

33. Musselli C, Ragupathi G, Gilewski T, Panageas KS, Spinat Y, Livingston PO. Reevaluation of the cellular immune response in breast cancer patients vaccinated with MUC1. Intl J Cancer 2002; 97: 660-667.

34. Springer GF. T and Tn, general carcinoma autoantigens. Science 1984; 224:1198-1206.

35. Lloyd KO. Blood group antigens as markers for normal differentiation and malignant change in human tissues. Amer J Clin Pathol 1987; 87:129-139.

36. Itzkowitz S, Bloom EJ, Kokal, WA, Modin G, Hakomori S-I, Kim YS. Sialosyl Tn: a novel mucin antigen associated with prognosis in colorectal carcinoma patients. Cancer 1990; 66:1960-1966.

37. Cho S-H, Sahin A, Hortobagyi GN, Hittelman WN, Dhingra K. Sialyl-Tn antigen expression occurs early during human mammary carcinogenesis and is associated with high nuclear grade and aneuploidy. Cancer Res 1994; 54:6302-6305.

38. Thor A, Obuchi N, Szpak CA, Johnston WW, Schlom J. Distribution of oncofetal antigen tumor-associated glycoprotein-72 defined by monoclonal antibody B72.3. Cancer Res 1986; 46:3118-3124.

39. Longenecker BM, Willans DJ, MacLean GD, Suresh S, Noujaim AA. Monoclonal antibodies and synthetic tumor-associated glycoconjugates in the study of the expression of Thomsen-Friedenreich-like and Tn-like antigens on human cancers. J Natl Cancer Inst 1987; 78:489-496.

40. Contegiacomo A, Alimandi M, Muraro R, Pizzi C, Calderopoli R, De Marchis L, Sgambato A, Pettinato G, Petrella G, De Filippo MR, et al. Expression of epitopes of the tumor-associated glycoprotein 72 and clinicopathological correlations in mammary carcinomas. Eur J Cancer 1994; 30A:813-820.

41. Zhang S, Walberg LA, Ogata S, Itzkowitz SH, Koganty RR, Reddish M, Gandhi SS, Longenecker BM, Lloyd KO, Livingston PO. Immune sera and monoclonal antibodies define two configurations for the sialyl Tn tumor antigen. Cancer Res 1995; 55:3364-3368.

42. Kostakoglu L, Divgi CR, Gilewski T, Theodoulou M, Schlom J, Larson SM. Phase II radioimmunotherapy (RIT) trial with I-131 labeled monoclonal antibody CC49 in Tag-72 expressing breast cancer. J Nucl Med 1994; 35(Suppl):234.

43. Larson SM, Carrasquillo JA, Colcher DC, Yokoyama K, Reynolds JC, Bacharach SA, Raubitchek A, Pace L, Finn RD, Rotman M. Estimates of radiation absorbed dose for intraperitoneally administered iodine-131 radiolabeled B72.3 monoclonal antibody in patients with peritoneal carcinomatosis. J Nucl Med 1991; 32:1661-1667.

44. MacLean GD, McEwan A, Noujaim AA, Sykes TR, Suresh MR, Catz Z, Hooper HR, Longenecker BM. A novel strategy for cancer immunoscinitgrapy. Antibody Immunoconj Radiopharmaceut 1989; 2:15.

45. Itzkowitz SH, Yuan M, Montgomery CK, Kjeldsen T, Takahashi HK, Bigbee WK, Kim YS. Expression of Tn, sialosyl-Tn, and T antigens in human colon cancer. Cancer Res 1989; 49:197-204.

46. MacLean GD, Reddish MA, Bowen-Yacyshyn MB, Poppema S, Longenecker BM. Active specific immunotherapy against adenocarcinomas. Cancer Invest 1994; 12:46-56.

47. Fung PYS, Madej M, Koganty RR, Longenecker BM. Active specific immunotherapy of a murine mammary adenocarcinoma using a synthetic tumor-associated glycoconjugate. Cancer Res 1990; 50:4308-4314.

48. Lackie PM, Zuber C, Roth J. Polysialic acid of the neural cell adhesion molecule (N-CAM) is widely expressed during organogenesis in mesodermal and endodermal derivatives. Differentiation 1994; 57:119-131.

49. Komminoth P, Roth J, Lackie PM, Bitter-Suermann D, Heintz PU. Polysialic acid of the neural cell adhesion molecule distinguishes small cell lung carcinoma from carcinoids. Am J Pathol 1991; 139:297-304.

50. Hayrinen J, Jennings H, Raff HV, Rougon G, Hanai N, Gerardy-Schahn R, Finne J. Antibodies to polysialic acid and its N-propyl derivative: binding properties and interaction with human embryonal brain glycopeptides. J Infect Dis 1995; 171:1481-1490.

51. MacLean GD, Reddish M, Koganty RR, Wong T, Gandhi S, Smolenski M, Samuel J, Nabholtz JM, Longenecker BM. Immunization of breast cancer patients using a synthetic sialyl-Tn glycoconjugate plus Detox adjuvant. Cancer Immunol Immunother 1993; 36:215-222.

52. 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.

53. Ferrone, S. Tumor escape mechanisms. Seminars Cancer Biol 2002;12:1-86.

54. Gottlinger HG, Funke I, Johnson JP, Gokel JM, Riethmuller G. The epithelial cell surface antigen 17-1A, a target for antibody-mediated tumor therapy: its biochemical nature, tissue distribution and recognition by different monoclonal antibodies. Int J Cancer 1986; 38:47-53.

55. Szala S, Froehlich M, Scollon M, Kasai Y, Steplewski Z, Koprowski H, Linnenbach AJ. Molecular cloning of cDNA for the carcinoma associated antigen GA733.2. Proc Natl Acad Sci USA 1990; 87:3542-3546.

56. LoBuglio AF, Saleh MN, Lee J, Khazaeli MB, Carrano R, Holden H, Wheeler R. Phase I trial of multiple large doses of murine monoclonal antibody CO17-1A. I. Clinical aspects. J Natl Cancer Inst 1988; 80:932-936.

57. Riethmuller G, Schneider-Gadicke E, Schlimok G, Schmiegel W, Raab R, Hoffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R, Buggisch P, Witte J, The German Cancer Aid 17-1A Study Group. Randomized trial of monoclonal antibody for adjuvant therapy of resected Dukes' C colorectal carcinoma. Lancet 1994; 343:1177-1183.

58. Somasundaram R, Zaloudik J, Jacob L, Benden A, Sperlagh M, Hart E, Marks G, Kane M, Mastrangelo M, Herlyn D. Induction of antigen-specific T and B cell immunity in colon carcinoma patients by antiidiotype antibody. J Immunol 1995; 155:3253-3261.

59. Yin WT, Dnistrian A, Lloyd KO. Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene. Intl J Cancer 2002; 98:737-740.

60. Zhang S, Graeber LA, Helling F, Ragupathi G, Adluri S, Lloyd KO, Livingston PO. Augmenting the immunogenicity of synthetic MUC1 peptide vaccines in mice. Cancer Res 1996; 56:3315-3319.

61. Livingston PO, Zhang S, Walberg L, Ragupathi G, Helling F, Fleischer M. Tumor cell reactivity mediated by IgM antibodies in sera from melanoma patients vaccinated with GM2-KLH is increased by IgG antibodies. Cancer Immunol Immunother 1997; 43:324-330.

62. Livingston PO, Calves MJ, Natoli Jr EJ. Approaches to augmenting the immunogenicity of the ganglioside GM2 in mice: purified GM2 is superior to whole cells. J Immunol 1987; 138:1524-1529.

63. Helling F, Zhang A, Shang A, Adluri S, Calves M, Koganty RR, Longenecker BM, Oettgen HF, Livingston PO. GM2-KLH conjugate vaccine: increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res 1995; 55:2783-2788.

64. Livingston PO, Adluri S, Helling F, Yao T-J, Kensil CR, Newman MJ, Marciani, D. Phase I trial of immunological adjuvant QS-21 with a GM2 ganglioside-KLH conjugate vaccine in patients with malignant melanoma. Vaccine 1994; 12:1275-1280.

65. Kim S-K, Ragupathi G, Cappello S, Kagan E, Livingston PO. Effect of immunological adjuvant combinations on the antibody and T-cell response to vaccination with MUC1-KLH and GD3-KLH conjugates. Vaccine 2000; 19:530-537.

66. Ritter G, Boosfeld E, Markstein E, Yu RK, Ren S, Oettgen HF, Old LJ, Livingston PO. Biochemical and serological characteristics of natural 9-O-acetyl GD3 from human melanoma and bovine buttermilk and chemically O-acetylated GD3. Cancer Res 1990; 50:1403-1410.

67. Ritter G, Boosfeld E, Calves MJ, Oettgen HF, Old LJ, Livingston PO. 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. Immunobiol 1990; 182:32-43.

68. Ritter G, Boosfeld E, Adluri R, Calves M, Oettgen HF, Old LJ, Livingston PO. Antibody response to immunization with ganglioside GD3 and GD3 congeners (lactones, amide and gangliosidol) in patients with malignant melanoma. Int J Cancer 1991; 48:379-385.

69. Ritter G, Ritter-Boosfeld E, Adluri R, Calves M, Ren S, Yu RK, Oettgen HF, Old LJ, Livingston PO. Analysis of the antibody response to immunization with purified O-acetyl GD3 gangliosides in patients with malignant melanoma. Int J Cancer 1995; 62:1-5.

70. Helling F, Shang A, Calves M, Zhang S, Ren S, Yu RK, Oettgen HF, Livingston PO. GD3 vaccines for melanoma: superior immunogenicity of keyhole limpet hemocyanin conjugate vaccines. Cancer Res 1994; 54:197-203.

71. Kensil CR, Patel U, Lennick M, Marciani D. Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex. J Immunol 1982; 12:91-96.

72. Livingston PO, Natoli Jr EJ, Calves M, Stockert E, Oettgen HF, Old LJ. Vaccines containing purified GM2 ganglioside elicit GM2 antibodies in melanoma patients. Proc Natl Acad Sci USA 1987; 84:29112915.

73. Kirkwood J, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, Rao U. High-dose interferon Alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E16954/ S9512/C50901. J Clin Immuno 2001; 19:2370-2380.

74. Dickler MN, Ragupathi G, Liu NX, Musselli C, Martino DJ, Miller VA, Kris MG, Brezicka FT, Livingston PO, Grant SC. Immunogenicity of the fucosyl-GM1-keyhole limpet hemocyanin (KLH) conjugate vaccine in patients with small cell lung cancer. Cancer Res 1999; 5:2773-2779.

75. Nores GA, Dohi T, Taniguchi M, Hakomori SI. Density-dependent recognition of cell surface GM3 by a certain anti-melanoma antibody, and GM3 lactone as a possible immunogen. J Immunol 1987; 139:3171.

76. Bilodeau MT, Park TK, Hu S, Tandolph JT, Danishefsky SJ, Livingston PO, Zhang S. Total synthesis of a human breast tumor associated antigen. J Amer Chem Soc 1995; 117:7840-7841.

77. Ragupathi G, Park TK, Zhang S, Kim IJ, Graeber K, Adluri S, Lloyd KO, Danishefsky SJ, Livingston PO. Immunization of mice with the synthetic hexasaccharide Globo H results in antibodies against human cancer cells. Angew Chem Int Ed Engl 1997; 36:125-128.

78. Behar V, Danishefsky SJ. A highly convergent synthesis of the Lewis-Y blood group determinant in conjugatable form. Angew Chem Int Ed Engl 1994; 33:1468-1470.

79. Ragupathi G, Slovin SF, Adluri S, Sames D, Kim I-J, Kim HM, Spassova M, Bornmann WG, Lloyd KO, Scher HI, Livingston PO, Danishefsky SJ. A fully synthetic globo H carbohydrate vaccine induces a focused humoral response in prostate cancer patients: a proof of principle. Angew Chem Intl Ed Engl 1999; 38:563-566.

80. Kudryashov V, Kim HM, Ragupathi G, Danishefsky SJ, Livingston PO, Lloyd KO. Immunogenicity of synthetic conjugates of Lewisy oligosaccharide with protein in mice: towards the design of anticancer vaccines. Cancer Immunol Immunother 1998; 45:281-286.

81. Slovin SF, Ragupathi G, Adluri S, Ungers G, Terry K, Kim S, Spassova M, Bornmann, WG, Fazzari M, Dantis L, Olkiewicz K, Lloyd KO, Livingston PO, Danishefsky SJ, Scher HI. Carbohydrate vaccines in cancer: immunogenicity of a fully synthetic Globo H hexasaccharide conjugate in man. Proc Natl Acad Sci USA 1999; 96:5710-5715.

82. Sabbatini P, Kudryashov V, Ragupathi G, Danishefsky S, Livingston PO, Bornmann W, Spassova M, Zatorski A, Spriggs D, Aghajanian C, Soignet S, Peyton M, O'Flaherty C, Curtin J, Lloyd KO. Immunization of ovarian cancer patients with a synthetic LewisY-protein conjugate vaccine: a phase 1 trial. Int J Cancer 2000; 87:79-85.

83. Gilewski T, Ragupathi G, Bhuta S, Williams LJ, Musselli C, Zhang XF, Bencsath KP, Panageas KS, Chin J, Norton L, Houghton AN, Livingston PO, Danishefsky SJ. Immunization of metastatic breast cancer patients with a fully synthetic globo H conjugate: a phase I trial. Proc Natl Acad Sci USA 2001; 98:3270-3275.

84. Adluri S, Helling F, Calves MJ, Lloyd KO, Livingston PO. Immunogenicity of synthetic TF- and sTn-KLH conjugates in colorectal carcinoma patients. Cancer Immunol Immunother 1995; 41:185-192.

85. MacLean GD, Bowen-Yacyshyn MB, Samuel J, Meikle A, Stuart G, Nation J, Poppema S, Jerry M, Koganty RR, Wong T, Longenecker BM. Active immunization of human ovarian cancer patients against a common carcinoma (Thomsen-Friedenreich) determinant using a synthetic carbohydrate antigen. J Immunother 1992; 11:292-305.

86. Livingston PO, Koganty RR, Longenecker BM, Lloyd KO, Calves M. 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. Vaccine Res 1992; 1: 99-109.

87. Nakada H, Inoue M, Numata Y, Tanaka N, Funakoshi I, Fukui S, Mellors A, Yamashina I. Epitopic structure of Tn glycophorin A for an anti-Tn antibody (MLS 128). Proc Natl Acad Sci USA 1993; 90:2495-2499.

88. Kurosaka A, Kitagawa H, Fukui S, Numata Y, Nakada H, Funakoshi I, Kawasaki T, Ogawa T, Iijima H, Yamashina I. A monoclonal antibody that recognizes a cluster of a disaccharide, NeuAca2-6GalNAc, in mucin-type glycoproteins. J Biol Chem 1988; 263:8724-8726.

89. Springer GF, Desai PR, Tegtmeyer H, Spencer BD, Scanlon EF. Pancarcinoma T/Tn antigen detects human carcinoma long before biopsy does and its vaccine prevents breast carcinoma recurrence. Ann NY Acad Sci 1993; 690:355-357.

90. Springer, GF. Immunoreactive T and Tn epitopes in cancer diagnosis, prognosis, and immunotherapy. J Mol Med 1997; 75:594-602.

91. MacLean GD, Miles DW, Rubens RD, Reddish MA, Longenecker BM. Enhancing the effect of Theratope STn-KLH cancer vaccine in patients with metastatic breast cancer by pretreatment with low-dose intravenous cyclophosphamide. J Immunother 1996;19:309-316.

92. Pon RA, Lussier M, Yang Q-L, Jennings HJ. N-Propionylated group B meningococcal polysaccharide mimics a unique bactericidal capsular epitope in group B Neisseria menigitidis. J Exp Med 1997; 185: 1929-1938.

93. Colten HR, Rosen FS. Complement deficiencies. Ann Rev Immunol 1992; 10:809-834.

94. Ragupathi G, Meyers M, Adluri S, Howard L, Musselli C, Livingston PO. Induction of antibodies against GD3 ganglioside in melanoma patients by vaccination with GD3-lactone-KLH conjugate plus immunological adjuvant QS-21. Int J Cancer 2000;85:659-666.

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Detoxification and Weight Loss

Detoxification and Weight Loss

Detoxification is something that is very important to the body, but it is something that isn't understood well. Centuries ago, health masters in the East understood the importance of balancing and detoxifying the body. It's something that Western medicine is only beginning to understand.

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