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Y. Hosokawa - One of the best experts on this subject based on the ideXlab platform.
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Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein
Leukemia, 2006Co-Authors: M Nakagawa, M Seto, Y. HosokawaAbstract:At least three recurrent chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), involving the API2-MALT1 fusion protein, BCL10 and MALT1, have been implicated in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma. Several lines of evidence indicated that both BCL10 and MALT1 are required for nuclear factor kappa B (NF- κ B) activation by antigen receptor stimulation in lymphocytes, and API2-MALT1 can bypass this BCL10/MALT1 signaling pathway. Nuclear factor kappa B activation may contribute to antiapoptotic effect through NF- κ B-mediated upregulation of apoptotic inhibitor genes. We recently demonstrated that API2-MALT1 can induce transactivation of the API2 gene through NF- κ B activation, thus highlighting a positive feedback-loop mechanism of self-activation by upregulating its own expression in t(11;18) MALT lymphomas. We also demonstrated that API2-MALT1 possesses an antiapoptotic effect, in part, through its direct interaction with apoptotic regulators. These findings therefore led us to hypothesize that the antiapoptotic effect by API2-MALT1 may be mediated by its interaction with apoptotic regulators, on the one hand, and by NF- κ B-mediated upregulation of apoptotic inhibitor genes on the other. We also found that BCL10 and MALT1 are shuttling between nucleus and cytoplasm, and that MALT1 can regulate the subcellular location of BCL10.
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Anti-apoptotic action of API2-MALT1 fusion protein involved in t(11;18)(q21;q21) MALT lymphoma
Apoptosis, 2005Co-Authors: Y. HosokawaAbstract:At least three distinct chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) involving the API2 (also known as c-IAP2)-MALT1 fusion protein, BCL10, and MALT1, respectively, have been implicated in the molecular pathogenesis of mucosa associated lymphoid tissue (MALT) lymphoma. Our findings showed that several variants of the API2-MALT1 fusion protein can occur in patients with t(11;18)(q21;q21), and that API2-MALT1 can potently enfance activation of nuclear factor (NF)- κ B signaling, which may be relevant to the pathogenesis of MALT lymphomas. We also found that MALT1 is rapidly degraded via the ubiquitin-proteasome pathway, as is the case with API2, but upon the synthesis of fusion, API2-MALT1 becomes stable against this pathway. This stability of API2-MALT1 may thus result in inappropriate nuclear factor (NF)- κ B activation, thereby contributing to the pathogenesis of MALT lymphoma. Recent biochemical and genetic studies have clearly shown that BCL10 and MALT1 form a physical and functional complex and are both required for NF- κ B activation by antigen receptor stimulation in T and B lymphocytes. It has also been shown that CARMA1, a newly discovered member of the membrane-associated guanylate kinase (MAGUK) families, is critical for antigen receptor-stimulated NF- κ B activation. It can be assumed that API2-MALT1 can bypass this normal BCL10/MALT1 cellular signaling pathway linked to NF- κ B activation, thereby inducing antigen receptor-independent proliferation of lymphocytes. Furthermore, BCL10/MALT1- and API2-MALT1-induced NF- κ B activation may contribute to anti-apoptotic action probably through NF- κ B-mediated upregulation of apoptotic inhibitor genes. We recently provided direct evidence that API2-MALT1 indeed exerts anti-apoptotic action, in part, through its direct interaction with apoptotic regulators including Smac. Taken together, these findings prompt us to hypothesize that the anti-apoptotic action of API2-MALT1 may be mediated partly by the direct interaction with apoptotic regulators as well as partly by upregulation of apoptotic inhibitor genes. Further studies can be expected to stimulate research into the development of therapeutic drugs that specifically inhibit the antigen receptor signaling-stimulated NF- κ B activation pathway: such molecule targeting drugs should be useful for interfering with inappropriate proliferation of lymphocytes associated with inflammatory and neoplastic disorders.
Philip O Livingston - One of the best experts on this subject based on the ideXlab platform.
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Fully S ynthetic C arbohydrate-Bas ed V accines i n B iochemically Relapsed P rostate C ancer: C linical T rial R esults With - N -Acetylgalactosa mine- O -Serine/Threonin e Conjugate V accine
2020Co-Authors: Susan F. Slovin, Govindaswami Ragupathi, Cristina Musselli, Krystyna Olkiewicz, David Verbel, Scott D. Kuduk, Jacob B. Schwarz, Dalibor Sames, Samuel J. Danishefsky, Philip O LivingstonAbstract:Purpose: We report the synthesis of a mucin-related O-linked glycopeptide, -N-acetylgalactosamine-O-serine/ threonine (Tn), which is highly simplistic in its structure and can induce a relevant humoral response when given in a trimer or clustered (c) formation. We tested for an antitumor effect, in the form of a change in the posttreatment versus pretreatment prostate-specific antigen (PSA) slopes, that might serve as a surrogate for effectiveness of vaccines in delaying the time to radiographic progression. Methods: We compared the antibody response to immunization with two conjugates, Tn(c)-keyhole limpet hemocyanin (KLH) and Tn(c)-palmitic acid (PAM) with the saponin immunologic adjuvant QS21, in a phase I clinical trial in patients with biochemically relapsed prostate cancer. Patients received Tn(c)-KLH vaccine containing either 3, 7, or 15 g of Tn(c) per vaccination. Ten patients received 100 g of Tn(c)-PAM. QS21 was included in all vaccines. Five vaccinations were administered subcutaneously during 26 weeks with an additional booster vaccine at week 50. Results: Tn(c), when given with the carrier molecule KLH and QS21, stimulated the production of high-titer immunoglobulin M (IgM) and IgG antibodies. Inferior antibody responses were seen with T(c)-PAM. There was no evidence of enhanced immunogenicity with increasing doses of vaccine. An antitumor effect in the form of a decline in posttreatment versus pretreatment PSA slopes was also observed. Conclusion: A safe synthetic conjugate vaccine in a trimer formation was developed that can break immunologic tolerance by inducing specific humoral responses. It seemed to affect the biochemical progression of the disease as determined by a change in PSA log slope. J Clin Oncol 21:4292-4298. © 2003 by American Society of Clinical Oncology.
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Fully Synthetic Carbohydrate-Based Vaccines in Biochemically Relapsed Prostate Cancer: Clinical Trial Results With α-N-Acetylgalactosamine-O-Serine/Threonine Conjugate Vaccine
Journal of Clinical Oncology, 2003Co-Authors: Susan F. Slovin, Govindaswami Ragupathi, Cristina Musselli, Krystyna Olkiewicz, David Verbel, Scott D. Kuduk, Jacob B. Schwarz, Dalibor Sames, Samuel J. Danishefsky, Philip O LivingstonAbstract:Purpose: We report the synthesis of a mucin-related O-linked glycopeptide, α-N-acetylgalactosamine-O-serine/threonine (Tn), which is highly simplistic in its structure and can induce a relevant humoral response when given in a trimer or clustered (c) formation. We tested for an antitumor effect, in the form of a change in the posttreatment versus pretreatment prostate-specific antigen (PSA) slopes, that might serve as a surrogate for effectiveness of vaccines in delaying the time to radiographic progression. Methods: We compared the antibody response to immunization with two conjugates, Tn(c)-keyhole limpet hemocyanin (KLH) and Tn(c)-palmitic acid (PAM) with the saponin immunologic adjuvant QS21, in a phase I clinical trial in patients with biochemically relapsed prostate cancer. Patients received Tn(c)-KLH vaccine containing either 3, 7, or 15 μg of Tn(c) per vaccination. Ten patients received 100 μg of Tn(c)-PAM. QS21 was included in all vaccines. Five vaccinations were administered subcutaneously durin...
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induction of antibodies against gm2 ganglioside by immunizing melanoma patients using gm2 keyhole limpet hemocyanin QS21 vaccine a dose response study
Clinical Cancer Research, 2000Co-Authors: Paul B Chapman, D M Morrissey, K S Panageas, W B Hamilton, C Zhan, Alicia N Destro, Lawrence J Williams, R J Israel, Philip O LivingstonAbstract:In a previous randomized Phase III trial (P. O. Livingston et al. , J. Clin. Oncol., 12: 1036–1044, 1994), we demonstrated that immunization with GM2 and bacille Calmette-Guerin reduced the risk of relapse in stage III melanoma patients who were free of disease after surgical resection and who had no preexisting anti-GM2 antibodies. That vaccine formulation induced IgM anti-GM2 antibodies in 74% but induced IgG anti-GM2 antibodies in only 10% of the patients. To optimize the immune response against GM2, a reformulated vaccine was produced conjugating GM2 to keyhole limpet hemocyanin (KLH) and using the adjuvant QS21 (GM2-KLH/QS21). In pilot studies, 70 μg of vaccine induced IgG anti-GM2 antibodies in 76% of the patients. We wished to define the lowest vaccine dose that induced consistent, high-titer IgM and IgG antibodies against GM2. Fifty-two melanoma patients who were free of disease after resection but at high risk for relapse were immunized with GM2-KLH/QS21 vaccine at GM2 doses of 1, 3, 10, 30, or 70μ g on weeks 1, 2, 3, 4, 12, 24, and 36. Serum collected at frequent and defined intervals was tested for anti-GM2 antibodies. Overall, 88% of the patients developed IgM anti-GM2 antibodies; 71% also developed IgG anti-GM2 antibodies. GM2-KLH doses of 3–70 μg seemed to be equivalent in terms of peak titers and induction of anti-GM2 antibodies. At the 30-μg dose level, 50% of the patients developed complement fixing anti-GM2 antibodies detectable at a serum dilution of 1:10. We conclude that the GM2-KLH/QS21 formulation is more immunogenic than our previous formulation and that 3 μg is the lowest dose that induces consistent, high-titer IgM and IgG antibodies against GM2.
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Induction of Antibodies against GM2 Ganglioside by Immunizing Melanoma Patients Using GM2-Keyhole Limpet Hemocyanin + QS21 Vaccine: A Dose-Response Study
Clinical Cancer Research, 2000Co-Authors: Paul B Chapman, D M Morrissey, K S Panageas, W B Hamilton, C Zhan, Alicia N Destro, Lawrence J Williams, R J Israel, Philip O LivingstonAbstract:In a previous randomized Phase III trial (P. O. Livingston et al. , J. Clin. Oncol., 12: 1036–1044, 1994), we demonstrated that immunization with GM2 and bacille Calmette-Guerin reduced the risk of relapse in stage III melanoma patients who were free of disease after surgical resection and who had no preexisting anti-GM2 antibodies. That vaccine formulation induced IgM anti-GM2 antibodies in 74% but induced IgG anti-GM2 antibodies in only 10% of the patients. To optimize the immune response against GM2, a reformulated vaccine was produced conjugating GM2 to keyhole limpet hemocyanin (KLH) and using the adjuvant QS21 (GM2-KLH/QS21). In pilot studies, 70 μg of vaccine induced IgG anti-GM2 antibodies in 76% of the patients. We wished to define the lowest vaccine dose that induced consistent, high-titer IgM and IgG antibodies against GM2. Fifty-two melanoma patients who were free of disease after resection but at high risk for relapse were immunized with GM2-KLH/QS21 vaccine at GM2 doses of 1, 3, 10, 30, or 70μ g on weeks 1, 2, 3, 4, 12, 24, and 36. Serum collected at frequent and defined intervals was tested for anti-GM2 antibodies. Overall, 88% of the patients developed IgM anti-GM2 antibodies; 71% also developed IgG anti-GM2 antibodies. GM2-KLH doses of 3–70 μg seemed to be equivalent in terms of peak titers and induction of anti-GM2 antibodies. At the 30-μg dose level, 50% of the patients developed complement fixing anti-GM2 antibodies detectable at a serum dilution of 1:10. We conclude that the GM2-KLH/QS21 formulation is more immunogenic than our previous formulation and that 3 μg is the lowest dose that induces consistent, high-titer IgM and IgG antibodies against GM2.
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Clinical Trials with a Polyvalent Breast cancer Vaccine
1998Co-Authors: Philip O LivingstonAbstract:Abstract : Preclinical studies with passively administered monoclonal antibodies or vaccine induced antibodies against glycolipid and mucin antigens have protected mice from tumor recurrence, even when treatment was initiated after tumor challenge. This timing is comparable to the adjuvant setting in the clinic. The glycolipid LeY and mucin MUC1 are expressed at the cell surface of most breast cancer cells in over 80% of breast cancer biopsy specimens. The optimal approach for antibody induction against these antigens has been conjugation to the immunogenic carrier molecule KLH and mixture with the potent immunological adjuvant QS21. The LeY-KLH and MUC1-KLH plus QS-21 vaccines prepared and tested over the last year have resulted in high titer antibodies against the synthetic antigens which were of relatively modest titer against tumor cells expressing these antigens. While these vaccines could be included in future polyvalent vaccines, it is our impression that we can augment the relevant immunogenicity by the modifications proposed which should make the immunogens more closely resemble the natural antigens. Consequently, glycosylated MUC1 peptides and LeY clusters will be conjugated to KLH, mixed with QS21, and tested over the next year.
A D M Rees - One of the best experts on this subject based on the ideXlab platform.
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immunization with human immunodeficiency virus type 1 rgp120w61d in QS21 mpl adjuvant primes t cell proliferation and c c chemokine production to multiple epitopes within variable and conserved domains of gp120w61d
The Journal of Infectious Diseases, 1999Co-Authors: Gareth J Jones, Paul Von Hoegen, Jonathan Weber, A D M ReesAbstract:Human immunodeficiency virus type I (HIV-1) gp120 W61D -specific T cell lines (TCL) were generated from an HIV-1-seronegative volunteer who received rgp120 W61D in QS21/MPL adjuvant with emulsion. TCL were challenged with pools of consecutive, overlapping peptides spanning the gp120 W61D sequence and then with the individual peptides of the immunostimulatory pool. T cell epitopes were found within both variable and conserved domains, and there was no evidence of a single immunodominant epitope. The two most frequently recognized peptides were located in the C1 domain and in the C-terminal region of the V3 loop. Several TCL were shown to recognize multiple peptides from nonoverlapping regions. Peptides from both conserved and variable domains were capable of inducing MIP-1α, MIP-1β, and RANTES production. When tested against the equivalent peptide from the HIV-1 IIIB sequence, however, TCL were able to tolerate only minor conserved changes in the amino acid sequence.
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Immunization with Human Immunodeficiency Virus Type 1 rgp120W61D in QS21/MPL Adjuvant Primes T Cell Proliferation and C-C Chemokine Production to Multiple Epitopes within Variable and Conserved Domains of gp120W61D
The Journal of Infectious Diseases, 1999Co-Authors: Gareth J Jones, Paul Von Hoegen, Jonathan Weber, A D M ReesAbstract:Human immunodeficiency virus type I (HIV-1) gp120 W61D -specific T cell lines (TCL) were generated from an HIV-1-seronegative volunteer who received rgp120 W61D in QS21/MPL adjuvant with emulsion. TCL were challenged with pools of consecutive, overlapping peptides spanning the gp120 W61D sequence and then with the individual peptides of the immunostimulatory pool. T cell epitopes were found within both variable and conserved domains, and there was no evidence of a single immunodominant epitope. The two most frequently recognized peptides were located in the C1 domain and in the C-terminal region of the V3 loop. Several TCL were shown to recognize multiple peptides from nonoverlapping regions. Peptides from both conserved and variable domains were capable of inducing MIP-1α, MIP-1β, and RANTES production. When tested against the equivalent peptide from the HIV-1 IIIB sequence, however, TCL were able to tolerate only minor conserved changes in the amino acid sequence.
Martine Anne Cecile Wettendorff - One of the best experts on this subject based on the ideXlab platform.
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vaccine adjuvant systems containing monophosphoryl lipid a and QS21 induce strong and persistent humoral and t cell responses against hepatitis b surface antigen in healthy adult volunteers
Vaccine, 2008Co-Authors: Pierre Vandepapelière, Yves Horsmans, Philippe Moris, Marcelle Van Mechelen, Michele Janssens, Marguerite Koutsoukos, Pascale Van Belle, Frederic Clement, Emmanuel Hanon, Martine Anne Cecile WettendorffAbstract:A randomised, double-blind study assessing the potential of four adjuvants in combination with recombinant hepatitis B surface antigen has been conducted to evaluate humoral and cell-mediated immune responses in healthy adults after three vaccine doses at months 0, 1 and 10. Three Adjuvant Systems (AS) contained 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and QS21, formulated either with an oil-in-water emulsion (AS02B and AS02V) or with liposomes (AS01B). The fourth adjuvant was CpG oligonucleotide. High levels of antibodies were induced by all adjuvants, whereas cell-mediated immune responses, including cytolytic T cells and strong and persistent CD4(+) T cell response were mainly observed with the three MPL/QS21-containing Adjuvant Systems. The CD4(+) T cell response was characterised in vitro by vigorous lymphoproliferation, high IFN-gamma and moderate IL-5 production. Antigen-specific T cell immune response was further confirmed ex vivo by detection of IL-2- and IFN-gamma-producing CD4(+) T cells, and in vivo by measuring increased levels of IFN-gamma in the serum and delayed-type hypersensitivity (DTH) responses. The CpG adjuvanted vaccine induced consistently lower immune responses for all parameters. All vaccine adjuvants were shown to be safe with acceptable reactogenicity profiles. The majority of subjects reported local reactions at the injection site after vaccination while general reactions were recorded less frequently. No vaccine-related serious adverse event was reported. Importantly, no increase in markers of auto-immunity and allergy was detected over the whole study course. In conclusion, the Adjuvant Systems containing MPL/QS21, in combination with hepatitis B surface antigen, induced very strong humoral and cellular immune responses in healthy adults. The AS01B-adjuvanted vaccine induced the strongest and most durable specific cellular immune responses after two doses. These Adjuvant Systems, when added to recombinant protein antigens, can be fundamental to develop effective prophylactic vaccines against complex pathogens, e.g. malaria, HIV infection and tuberculosis, and for special target populations such as subjects with an impaired immune response, due to age or medical conditions.
Paul B Chapman - One of the best experts on this subject based on the ideXlab platform.
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induction of antibodies against gm2 ganglioside by immunizing melanoma patients using gm2 keyhole limpet hemocyanin QS21 vaccine a dose response study
Clinical Cancer Research, 2000Co-Authors: Paul B Chapman, D M Morrissey, K S Panageas, W B Hamilton, C Zhan, Alicia N Destro, Lawrence J Williams, R J Israel, Philip O LivingstonAbstract:In a previous randomized Phase III trial (P. O. Livingston et al. , J. Clin. Oncol., 12: 1036–1044, 1994), we demonstrated that immunization with GM2 and bacille Calmette-Guerin reduced the risk of relapse in stage III melanoma patients who were free of disease after surgical resection and who had no preexisting anti-GM2 antibodies. That vaccine formulation induced IgM anti-GM2 antibodies in 74% but induced IgG anti-GM2 antibodies in only 10% of the patients. To optimize the immune response against GM2, a reformulated vaccine was produced conjugating GM2 to keyhole limpet hemocyanin (KLH) and using the adjuvant QS21 (GM2-KLH/QS21). In pilot studies, 70 μg of vaccine induced IgG anti-GM2 antibodies in 76% of the patients. We wished to define the lowest vaccine dose that induced consistent, high-titer IgM and IgG antibodies against GM2. Fifty-two melanoma patients who were free of disease after resection but at high risk for relapse were immunized with GM2-KLH/QS21 vaccine at GM2 doses of 1, 3, 10, 30, or 70μ g on weeks 1, 2, 3, 4, 12, 24, and 36. Serum collected at frequent and defined intervals was tested for anti-GM2 antibodies. Overall, 88% of the patients developed IgM anti-GM2 antibodies; 71% also developed IgG anti-GM2 antibodies. GM2-KLH doses of 3–70 μg seemed to be equivalent in terms of peak titers and induction of anti-GM2 antibodies. At the 30-μg dose level, 50% of the patients developed complement fixing anti-GM2 antibodies detectable at a serum dilution of 1:10. We conclude that the GM2-KLH/QS21 formulation is more immunogenic than our previous formulation and that 3 μg is the lowest dose that induces consistent, high-titer IgM and IgG antibodies against GM2.
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Induction of Antibodies against GM2 Ganglioside by Immunizing Melanoma Patients Using GM2-Keyhole Limpet Hemocyanin + QS21 Vaccine: A Dose-Response Study
Clinical Cancer Research, 2000Co-Authors: Paul B Chapman, D M Morrissey, K S Panageas, W B Hamilton, C Zhan, Alicia N Destro, Lawrence J Williams, R J Israel, Philip O LivingstonAbstract:In a previous randomized Phase III trial (P. O. Livingston et al. , J. Clin. Oncol., 12: 1036–1044, 1994), we demonstrated that immunization with GM2 and bacille Calmette-Guerin reduced the risk of relapse in stage III melanoma patients who were free of disease after surgical resection and who had no preexisting anti-GM2 antibodies. That vaccine formulation induced IgM anti-GM2 antibodies in 74% but induced IgG anti-GM2 antibodies in only 10% of the patients. To optimize the immune response against GM2, a reformulated vaccine was produced conjugating GM2 to keyhole limpet hemocyanin (KLH) and using the adjuvant QS21 (GM2-KLH/QS21). In pilot studies, 70 μg of vaccine induced IgG anti-GM2 antibodies in 76% of the patients. We wished to define the lowest vaccine dose that induced consistent, high-titer IgM and IgG antibodies against GM2. Fifty-two melanoma patients who were free of disease after resection but at high risk for relapse were immunized with GM2-KLH/QS21 vaccine at GM2 doses of 1, 3, 10, 30, or 70μ g on weeks 1, 2, 3, 4, 12, 24, and 36. Serum collected at frequent and defined intervals was tested for anti-GM2 antibodies. Overall, 88% of the patients developed IgM anti-GM2 antibodies; 71% also developed IgG anti-GM2 antibodies. GM2-KLH doses of 3–70 μg seemed to be equivalent in terms of peak titers and induction of anti-GM2 antibodies. At the 30-μg dose level, 50% of the patients developed complement fixing anti-GM2 antibodies detectable at a serum dilution of 1:10. We conclude that the GM2-KLH/QS21 formulation is more immunogenic than our previous formulation and that 3 μg is the lowest dose that induces consistent, high-titer IgM and IgG antibodies against GM2.
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Immunization of melanoma patients with BEC2 anti-idiotypic monoclonal antibody that mimics GD3 ganglioside: enhanced immunogenicity when combined with adjuvant.
Clinical Cancer Research, 1996Co-Authors: M. Mccaffery, Philip O Livingston, Linda Williams, Alan N. Houghton, Paul B ChapmanAbstract:Previous attempts to immunize melanoma patients against GD3 ganglioside have been unsuccessful because of the poor immunogenicity of GD3. BEC2, an anti-idiotypic monoclonal antibody that mimics GD3, can induce anti-GD3 IgG in rabbits. Since clinical trials with BEC2 in melanoma patients demonstrated that BEC2 alone is not highly immunogenic, we have carried out sequential clinical trials exploring the use of two immunological adjuvants, BCG and QS21, administered with BEC2. Melanoma patients free of disease after surgical resection but at high risk for recurrence were immunized either with BEC2/BCG (14 patients) or BEC2/QS21 (6 patients). All patients developed high-titer IgG antibodies against BEC2, demonstrating that both adjuvants effectively enhanced the immunogenicity of BEC2. Anti-GD3 antibodies were induced in 3 of 14 patients immunized with BEC2/BCG; no patient immunized with BEC2/QS21 developed detectable anti-GD3 antibodies. After a median follow-up of 2.4 years, 71% of the patients immunized with BEC2/BCG remain alive and 64% are free of disease. In patients immunized with BEC2/BCG, no apparent association was observed between class II HLA type and either development of anti-GD3 antibodies or survival. We are encouraged by the results with BEC2/BCG, which suggest that further enhancement of the immune response to BEC2 will result in more frequent anti-GD3 antibody responses among immunized patients.