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Philip O Livingston - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and immunologic evaluation of vaccine adjuvant conjugates based on Qs 21 and tucaresol
Bioorganic & Medicinal Chemistry, 2014Co-Authors: Alberto Fernandeztejada, Philip O Livingston, Jeffrey R Gardner, Eric K Chea, Constantine George, Govind RagupathiAbstract:Immunoadjuvants are used to potentiate the activity of modern subunit vaccines that are based on molecular antigens. An emerging approach involves the combination of multiple adjuvants in a single formulation to achieve optimal vaccine efficacy. Herein, to investigate such potential synergies, we synthesized novel adjuvant conjugates based on the saponin natural product Qs-21 and the aldehyde tucaresol via chemoselective acylation of an amine at the terminus of the acyl chain domain in Qs saponin variants. In a preclinical mouse vaccination model, these Qs saponin–tucaresol conjugates induced antibody responses similar to or slightly higher than those generated with related Qs saponin variants lacking the tucaresol motif. The conjugates retained potent adjuvant activity, low toxicity, and improved activity–toxicity profiles relative to Qs-21 itself and induced IgG subclass profiles similar to those of Qs-21, indicative of both Th1 cellular and Th2 humoral immune responses. This study opens the door to installation of other substituents at the terminus of the acyl chain domain to develop additional Qs saponin conjugates with desirable immunologic properties.
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development of a minimal saponin vaccine adjuvant based on Qs 21
Nature Chemistry, 2014Co-Authors: Alberto Fernandeztejada, Philip O Livingston, Govind Ragupathi, Jeffrey R Gardner, Eric K Chea, Constantine George, Nagavarakishore Pillarsetty, Jason S LewisAbstract:Adjuvants are used to increase the immune response to molecular vaccines. A minimal synthetic variant of the saponin natural product Qs-21 has been developed as a potent, non-toxic adjuvant, enabling dissection of structural requirements in the triterpene domain and in vivo biodistribution studies to probe mechanisms of action.
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synthesis and preclinical evaluation of Qs 21 variants leading to simplified vaccine adjuvants and mechanistic probes
Journal of the American Chemical Society, 2012Co-Authors: Eric K Chea, Alberto Fernandeztejada, Michelle M Adams, Payal Damani, Philip O Livingston, Jeffrey R Gardner, Govind RagupathiAbstract:Qs-21 is a potent immunostimulatory saponin that is currently under clinical investigation as an adjuvant in various vaccines to treat infectious diseases, cancers, and cognitive disorders. Herein, we report the design, synthesis, and preclinical evaluation of simplified Qs-21 congeners to define key structural features that are critical for adjuvant activity. Truncation of the linear tetrasaccharide domain revealed that a trisaccharide variant is equipotent to Qs-21, while the corresponding disaccharide and monosaccharide congeners are more toxic and less potent, respectively. Modification of the acyl chain domain in the trisaccharide series revealed that a terminal carboxylic acid is well-tolerated while a terminal amine results in reduced adjuvant activity. Acylation of the terminal amine can, in some cases, restore adjuvant activity and enables the synthesis of fluorescently labeled Qs-21 variants. Cellular studies with these probes revealed that, contrary to conventional wisdom, the most highly adjuv...
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a pilot study of vaccination with sialyl lewisa slea keyhole limpet hemocyanin klh conjugate plus the immunologic adjuvant Qs 21 in metastatic breast cancer patients pts
Journal of Clinical Oncology, 2011Co-Authors: Adi Diab, Philip O Livingston, Govindaswami Ragupathi, Katherine S Panageas, Clifford A Hudis, Wolfgang W Scholz, Teresa GilewskiAbstract:2599 Background: The carbohydrate antigen sLea, recognized by the monoclonal antibody (mAb), CA19-9, is commonly expressed on breast cancer cells and is a potential target for vaccine therapy. Methods: The primary endpoints were safety and immunogenicity. Secondary endpoint was presence of circulating tumor cells (CTC) pre and post injection. Pts received sLea (10 or 30 mcg) conjugated to KLH + 100 mcg Qs-21 via subcutaneous vaccination during weeks 1, 2, 3, 7, and 19. Pts with metastatic breast cancer with no evidence of disease or stable disease were eligible. Results: Seven pts were treated (10 mcg n=3, 30 mcg n=4), median age 45 years (range 31-65). Six pts were on hormone therapy during the study; 2 pts with no disease and 5 pts with stable disease. Six pts completed 5/5 planned injections. One pt received 4/5 injections. Overall the injections were well tolerated, with grade 1-2 local skin injection site reactions and grade 1 flu-like symptoms the most common toxicities. In 5/7 pts there were no CTC...
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natural and synthetic saponin adjuvant Qs 21 for vaccines against cancer
Expert Review of Vaccines, 2011Co-Authors: Govind Ragupathi, Jeffrey R Gardner, Philip O LivingstonAbstract:One of the most widely used and potent immunological adjuvants is a mixture of soluble triterpene glycosides purified from the soap bark tree (Quillaja saponaria). Despite challenges in production, quality control, stability and toxicity, the Qs-21 fraction from this extract has exhibited exceptional adjuvant properties for a range of antigens. It possesses an ability to augment clinically significant antibody and T-cell responses to vaccine antigens against a variety of infectious diseases, degenerative disorders and cancers. The recent synthesis of active molecules of Qs-21 has provided a robust method to produce this leading vaccine adjuvant in high purity as well as to produce novel synthetic Qs-21 congeners designed to induce increased immune responsiveness and decreased toxicity.
Alexander M.m. Eggermont - One of the best experts on this subject based on the ideXlab platform.
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adjuvant ganglioside gm2 klh Qs 21 vaccination versus observation after resection of primary tumor 1 5 mm in patients with stage ii melanoma results of the eortc 18961 randomized phase iii trial
Journal of Clinical Oncology, 2013Co-Authors: Alexander M.m. Eggermont, Stefan Suciu, Piotr Rutkowski, Jeremy Marsden, Mario Santinami, Philippa Corrie, Steinar Aamdal, Paolo A. Ascierto, Poulam M. Patel, Wim H. J. KruitAbstract:Purpose The GM2 ganglioside is an antigen expressed in the majority of melanomas. The GM2-KLH/Qs-21 vaccine induces high immunoglobulin M (IgM) and IgG antibody responses. The EORTC 18961 trial compared the efficacy of GM2-KLH/Qs-21 vaccination versus observation. Patients and Methods A total of 1,314 patients with a primary tumor 1.50 mm in thickness (T3-4N0M0; American Joint Committee on Cancer stage II) were randomly assigned to GM2-KLH/Qs-21 vaccination (n 657) or observation (n 657). Treatment consisted of subcutaneous injections once per week from week 1 to 4, then every 3 months for the first 2 years and every 6 months during the third year. Primary end point was relapse-free survival (RFS). Secondary end points were distant metastasisfree survival (DMFS) and overall survival (OS). Analyses were by intent to treat. Results After a median follow-up of 1.8 years, the trial was stopped at the second interim analysis for futility regarding RFS (hazard ratio [HR], 1.00; P .99) and detrimental outcome regarding OS (HR, 1.66; P .02). After a median follow-up of 4.2 years, we had recorded 400 relapses, nine deaths without relapse, a total of 236 deaths. At 4 years, the vaccination arm showed a decreased RFS rate of 1.2% (HR, 1.03; 95% CI, 0.84 to 1.25) and OS rate of 2.1% (HR, 1.16; 95% CI, 0.90 to 1.51). Toxicity was acceptable, with 4.6% of patients ending study participation because of toxicity.
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Adjuvant Ganglioside GM2-KLH/Qs-21 Vaccination Versus Observation After Resection of Primary Tumor > 1.5 mm in Patients With Stage II Melanoma: Results of the EORTC 18961 Randomized Phase III Trial
Journal of Clinical Oncology, 2013Co-Authors: Alexander M.m. Eggermont, Stefan Suciu, Piotr Rutkowski, Jeremy Marsden, Mario Santinami, Philippa Corrie, Steinar Aamdal, Paolo A. Ascierto, Poulam M. Patel, Wim H. J. KruitAbstract:Purpose The GM2 ganglioside is an antigen expressed in the majority of melanomas. The GM2-KLH/Qs-21 vaccine induces high immunoglobulin M (IgM) and IgG antibody responses. The EORTC 18961 trial compared the efficacy of GM2-KLH/Qs-21 vaccination versus observation. Patients and Methods A total of 1,314 patients with a primary tumor 1.50 mm in thickness (T3-4N0M0; American Joint Committee on Cancer stage II) were randomly assigned to GM2-KLH/Qs-21 vaccination (n 657) or observation (n 657). Treatment consisted of subcutaneous injections once per week from week 1 to 4, then every 3 months for the first 2 years and every 6 months during the third year. Primary end point was relapse-free survival (RFS). Secondary end points were distant metastasisfree survival (DMFS) and overall survival (OS). Analyses were by intent to treat. Results After a median follow-up of 1.8 years, the trial was stopped at the second interim analysis for futility regarding RFS (hazard ratio [HR], 1.00; P .99) and detrimental outcome regarding OS (HR, 1.66; P .02). After a median follow-up of 4.2 years, we had recorded 400 relapses, nine deaths without relapse, a total of 236 deaths. At 4 years, the vaccination arm showed a decreased RFS rate of 1.2% (HR, 1.03; 95% CI, 0.84 to 1.25) and OS rate of 2.1% (HR, 1.16; 95% CI, 0.90 to 1.51). Toxicity was acceptable, with 4.6% of patients ending study participation because of toxicity.
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randomized phase iii trial comparing postoperative adjuvant ganglioside gm2 klh Qs 21 vaccination versus observation in stage ii t3 t4n0m0 melanoma final results of study eortc 18961
Journal of Clinical Oncology, 2010Co-Authors: Alexander M.m. Eggermont, Stefan Suciu, Piotr Rutkowski, Philippa Corrie, Steinar Aamdal, Paolo A. Ascierto, Poulam M. Patel, J R Marsden, Alessandro Testori, Alan SpatzAbstract:8505 Background: In the largest adjuvant phase III study in stage II melanoma to date, EORTC 18961 assessed the efficacy and toxicity of ganglioside GM2-KLH/Qs-21 vaccination versus observation (OBS). Methods: Patients (Pts) were observed or received vaccine sc once weekly weeks 1-4, every 3 months from week 12 for first 2 years and every 6 months during third year (total of 14 vaccinations). Stratification factors at randomization were: Breslow thickness, ulceration, being staged yes vs no by sentinel node or elective lymph node dissection, sex and institution. Relapse-free survival (RFS) was the prespecified primary endpoint; distant metastasis-free survival (DMFS) and overall survival (OS) were secondary endpoints. An intent-to-treat analysis was performed. Results: Between March 2002 and December 2005, 1,314 pts entered the trial. Patient demographics showed excellent balance for prognostic factors. The second interim analysis was performed when 267 RFS events were reported. For the primary endpoint, ...
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Randomized phase III trial comparing postoperative adjuvant ganglioside GM2-KLH/Qs-21 vaccination versus observation in stage II (T3-T4N0M0) melanoma: Final results of study EORTC 18961.
Journal of Clinical Oncology, 2010Co-Authors: Alexander M.m. Eggermont, Stefan Suciu, Piotr Rutkowski, Philippa Corrie, Steinar Aamdal, Paolo A. Ascierto, Poulam M. Patel, J R Marsden, Alessandro Testori, Alan SpatzAbstract:8505 Background: In the largest adjuvant phase III study in stage II melanoma to date, EORTC 18961 assessed the efficacy and toxicity of ganglioside GM2-KLH/Qs-21 vaccination versus observation (OBS). Methods: Patients (Pts) were observed or received vaccine sc once weekly weeks 1-4, every 3 months from week 12 for first 2 years and every 6 months during third year (total of 14 vaccinations). Stratification factors at randomization were: Breslow thickness, ulceration, being staged yes vs no by sentinel node or elective lymph node dissection, sex and institution. Relapse-free survival (RFS) was the prespecified primary endpoint; distant metastasis-free survival (DMFS) and overall survival (OS) were secondary endpoints. An intent-to-treat analysis was performed. Results: Between March 2002 and December 2005, 1,314 pts entered the trial. Patient demographics showed excellent balance for prognostic factors. The second interim analysis was performed when 267 RFS events were reported. For the primary endpoint, ...
Govind Ragupathi - One of the best experts on this subject based on the ideXlab platform.
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Quillaja saponin variants with central glycosidic linkage modifications exhibit distinct conformations and adjuvant activities
Chemical Science, 2016Co-Authors: William E Walkowicz, Constantine George, Alberto Fernández-tejada, Francisco Corzana, Jesús Jiménez-barbero, Govind RagupathiAbstract:Immunological adjuvants such as the saponin natural product Qs-21 help stimulate the immune response to co-administered antigens and have become increasingly important in the development of prophylactic and therapeutic vaccines. However, clinical use of Qs-21 is encumbered by chemical instability, dose-limiting toxicity, and low-yielding purification from the natural source. Previous studies of structure–activity relationships in the four structural domains of Qs-21 have led to simplified, chemically stable variants that retain potent adjuvant activity and low toxicity in mouse vaccination models. However, modification of the central glycosyl ester linkage has not yet been explored. Herein, we describe the design, synthesis, immunologic evaluation, and molecular dynamics analysis of a series of novel Qs-21 variants with different linker lengths, stereochemistry, and flexibility to investigate the role of this linkage in saponin adjuvant activity and conformation. Despite relatively conservative structural modifications, these variants exhibit striking differences in in vivo adjuvant activity that correlate with specific conformational preferences. These results highlight the junction of the triterpene and linear oligosaccharide domains as playing a critical role in the immunoadjuvant activity of the Quillaja saponins and also suggest a mechanism of action involving interaction with a discrete macromolecular target, in contrast to the non-specific mechanisms of emulsion-based adjuvants.
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design synthesis and immunologic evaluation of vaccine adjuvant conjugates based on Qs 21 and tucaresol
Bioorganic & Medicinal Chemistry, 2014Co-Authors: Alberto Fernandeztejada, Philip O Livingston, Jeffrey R Gardner, Eric K Chea, Constantine George, Govind RagupathiAbstract:Immunoadjuvants are used to potentiate the activity of modern subunit vaccines that are based on molecular antigens. An emerging approach involves the combination of multiple adjuvants in a single formulation to achieve optimal vaccine efficacy. Herein, to investigate such potential synergies, we synthesized novel adjuvant conjugates based on the saponin natural product Qs-21 and the aldehyde tucaresol via chemoselective acylation of an amine at the terminus of the acyl chain domain in Qs saponin variants. In a preclinical mouse vaccination model, these Qs saponin–tucaresol conjugates induced antibody responses similar to or slightly higher than those generated with related Qs saponin variants lacking the tucaresol motif. The conjugates retained potent adjuvant activity, low toxicity, and improved activity–toxicity profiles relative to Qs-21 itself and induced IgG subclass profiles similar to those of Qs-21, indicative of both Th1 cellular and Th2 humoral immune responses. This study opens the door to installation of other substituents at the terminus of the acyl chain domain to develop additional Qs saponin conjugates with desirable immunologic properties.
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development of a minimal saponin vaccine adjuvant based on Qs 21
Nature Chemistry, 2014Co-Authors: Alberto Fernandeztejada, Philip O Livingston, Govind Ragupathi, Jeffrey R Gardner, Eric K Chea, Constantine George, Nagavarakishore Pillarsetty, Jason S LewisAbstract:Adjuvants are used to increase the immune response to molecular vaccines. A minimal synthetic variant of the saponin natural product Qs-21 has been developed as a potent, non-toxic adjuvant, enabling dissection of structural requirements in the triterpene domain and in vivo biodistribution studies to probe mechanisms of action.
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synthesis and preclinical evaluation of Qs 21 variants leading to simplified vaccine adjuvants and mechanistic probes
Journal of the American Chemical Society, 2012Co-Authors: Eric K Chea, Alberto Fernandeztejada, Michelle M Adams, Payal Damani, Philip O Livingston, Jeffrey R Gardner, Govind RagupathiAbstract:Qs-21 is a potent immunostimulatory saponin that is currently under clinical investigation as an adjuvant in various vaccines to treat infectious diseases, cancers, and cognitive disorders. Herein, we report the design, synthesis, and preclinical evaluation of simplified Qs-21 congeners to define key structural features that are critical for adjuvant activity. Truncation of the linear tetrasaccharide domain revealed that a trisaccharide variant is equipotent to Qs-21, while the corresponding disaccharide and monosaccharide congeners are more toxic and less potent, respectively. Modification of the acyl chain domain in the trisaccharide series revealed that a terminal carboxylic acid is well-tolerated while a terminal amine results in reduced adjuvant activity. Acylation of the terminal amine can, in some cases, restore adjuvant activity and enables the synthesis of fluorescently labeled Qs-21 variants. Cellular studies with these probes revealed that, contrary to conventional wisdom, the most highly adjuv...
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natural and synthetic saponin adjuvant Qs 21 for vaccines against cancer
Expert Review of Vaccines, 2011Co-Authors: Govind Ragupathi, Jeffrey R Gardner, Philip O LivingstonAbstract:One of the most widely used and potent immunological adjuvants is a mixture of soluble triterpene glycosides purified from the soap bark tree (Quillaja saponaria). Despite challenges in production, quality control, stability and toxicity, the Qs-21 fraction from this extract has exhibited exceptional adjuvant properties for a range of antigens. It possesses an ability to augment clinically significant antibody and T-cell responses to vaccine antigens against a variety of infectious diseases, degenerative disorders and cancers. The recent synthesis of active molecules of Qs-21 has provided a robust method to produce this leading vaccine adjuvant in high purity as well as to produce novel synthetic Qs-21 congeners designed to induce increased immune responsiveness and decreased toxicity.
Katherine S Panageas - One of the best experts on this subject based on the ideXlab platform.
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a pilot study of vaccination with sialyl lewisa slea keyhole limpet hemocyanin klh conjugate plus the immunologic adjuvant Qs 21 in metastatic breast cancer patients pts
Journal of Clinical Oncology, 2011Co-Authors: Adi Diab, Philip O Livingston, Govindaswami Ragupathi, Katherine S Panageas, Clifford A Hudis, Wolfgang W Scholz, Teresa GilewskiAbstract:2599 Background: The carbohydrate antigen sLea, recognized by the monoclonal antibody (mAb), CA19-9, is commonly expressed on breast cancer cells and is a potential target for vaccine therapy. Methods: The primary endpoints were safety and immunogenicity. Secondary endpoint was presence of circulating tumor cells (CTC) pre and post injection. Pts received sLea (10 or 30 mcg) conjugated to KLH + 100 mcg Qs-21 via subcutaneous vaccination during weeks 1, 2, 3, 7, and 19. Pts with metastatic breast cancer with no evidence of disease or stable disease were eligible. Results: Seven pts were treated (10 mcg n=3, 30 mcg n=4), median age 45 years (range 31-65). Six pts were on hormone therapy during the study; 2 pts with no disease and 5 pts with stable disease. Six pts completed 5/5 planned injections. One pt received 4/5 injections. Overall the injections were well tolerated, with grade 1-2 local skin injection site reactions and grade 1 flu-like symptoms the most common toxicities. In 5/7 pts there were no CTC...
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immunization of high risk breast cancer patients with clustered stn klh conjugate plus the immunologic adjuvant Qs 21
Clinical Cancer Research, 2007Co-Authors: Teresa Gilewski, Govind Ragupathi, Rao R Koganty, Katherine S Panageas, Maura N Dickler, Shemeeakah Powell, Sonal Bhuta, Jeannette Chineng, Clifford A Hudis, Larry NortonAbstract:Purpose: To determine the clinical toxicities and antibody response against sTn and tumor cells expressing sTn following immunization of high-risk breast cancer patients with clustered sTn-KLH [sTn(c)-KLH] conjugate plus Qs-21. Experimental Design: Twenty-seven patients with no evidence of disease and with a history of either stage IV no evidence of disease, rising tumor markers, stage II (≥4 positive axillary nodes), or stage III disease received a total of five injections each during weeks 1, 2, 3, 7, and 19. Immunizations consisted of sTn(c)-KLH conjugate containing 30, 10, 3, or 1 μg sTn(c) plus 100 μg Qs-21. Induction of IgM and IgG antibodies against synthetic sTn(c) and natural sTn on ovine submaxillary mucin were measured before and after therapy. Fluorescence-activated cell sorting analyses assessed reactivity of antibodies to LSC and MCF-7 tumor cells. Results: The most common toxicities were transient local skin reactions at the injection site and mild flu-like symptoms. All patients developed significant IgM and IgG antibody titers against sTn(c). Antibody titers against ovine submaxillary mucin were usually of lower titers. IgM reactivity with LSC tumor cells was observed in 21 patients and with MCF-7 cells in 13 patients. There was minimal IgG reactivity with LSC cells. Conclusion: Immunization with sTn(c)-KLH conjugate plus Qs-21 is well tolerated and immunogenic in high-risk breast cancer patients. Future trials will incorporate sTn(c) as a component of a multiple antigen vaccine.
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T-Cell Responses against Tyrosinase 368–376(370D) Peptide in HLA∗A0201+ Melanoma Patients: Randomized Trial Comparing Incomplete Freund’s Adjuvant, Granulocyte Macrophage Colony-stimulating Factor, and Qs-21 as Immunological Adjuvants
Clinical Cancer Research, 2002Co-Authors: Susanne G. Schaed, Philip O Livingston, Katherine S Panageas, Virginia M. Klimek, Cristina Musselli, Leah Butterworth, Linda Williams, Jonathan J. Lewis, Alan N HoughtonAbstract:We conducted a randomized trial in HLA∗A0201 + patientswith American Joint Committee on Cancer stage III or IV melanoma immunized with tyrosinase 368–376(370D) peptide and gp100 209–217(210M) peptide to compare the potency of three different adjuvants. Patients received 3 monthly immunizations with 500 μg of each peptide either with incomplete Freund’s adjuvant (IFA), Qs-21, or granulocyte macrophage colony-stimulating factor (GM-CSF). The primary end point was induction of IFN-γ release by CD8 + T cells against tyrosinase and gp100 peptides measured by enzyme-linked immunospot assays without in vitro prestimulation measured pretreatment, 2 and 8 weeks after the third vaccination. Four of 9 and 4 of 8 patients immunized using Qs-21 and GM-CSF, respectively, developed increased frequencies of CD8 + T cells against tyrosinase 370D peptide compared with 0 of 9 patients immunized using IFA ( P = 0.045). T-cell responses against a gp100-related peptide showed similar results, but their relevance to T-cell reactivity against native gp100 209–217 is uncertain. These results show that: ( a ) Qs-21 and GM-CSF are superior to IFA as immunological adjuvants for vaccination against tyrosinase 370D peptide; and ( b ) with appropriate adjuvants, increased frequencies of peptide-specific T cells after vaccination can be detected by enzyme-linked immunospot without prolonged prestimulation in vitro .
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t cell responses against tyrosinase 368 376 370d peptide in hla a0201 melanoma patients randomized trial comparing incomplete freund s adjuvant granulocyte macrophage colony stimulating factor and Qs 21 as immunological adjuvants
Clinical Cancer Research, 2002Co-Authors: Susanne G. Schaed, Philip O Livingston, Katherine S Panageas, Alan N Houghton, Virginia M. Klimek, Cristina Musselli, Leah Butterworth, Linda Williams, Jonathan J. Lewis, Paul B ChapmanAbstract:We conducted a randomized trial in HLA∗A0201 + patientswith American Joint Committee on Cancer stage III or IV melanoma immunized with tyrosinase 368–376(370D) peptide and gp100 209–217(210M) peptide to compare the potency of three different adjuvants. Patients received 3 monthly immunizations with 500 μg of each peptide either with incomplete Freund’s adjuvant (IFA), Qs-21, or granulocyte macrophage colony-stimulating factor (GM-CSF). The primary end point was induction of IFN-γ release by CD8 + T cells against tyrosinase and gp100 peptides measured by enzyme-linked immunospot assays without in vitro prestimulation measured pretreatment, 2 and 8 weeks after the third vaccination. Four of 9 and 4 of 8 patients immunized using Qs-21 and GM-CSF, respectively, developed increased frequencies of CD8 + T cells against tyrosinase 370D peptide compared with 0 of 9 patients immunized using IFA ( P = 0.045). T-cell responses against a gp100-related peptide showed similar results, but their relevance to T-cell reactivity against native gp100 209–217 is uncertain. These results show that: ( a ) Qs-21 and GM-CSF are superior to IFA as immunological adjuvants for vaccination against tyrosinase 370D peptide; and ( b ) with appropriate adjuvants, increased frequencies of peptide-specific T cells after vaccination can be detected by enzyme-linked immunospot without prolonged prestimulation in vitro .
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vaccination of high risk breast cancer patients with mucin 1 muc1 keyhole limpet hemocyanin conjugate plus Qs 21
Clinical Cancer Research, 2000Co-Authors: Teresa Gilewski, Shengle Zhang, Sucharita Adluri, Govindaswami Ragupathi, Katherine S Panageas, M E Moynahan, Alan N Houghton, Larry Norton, Philip O LivingstonAbstract:Our objective was to determine whether an immune response can be generated against MUC1 peptide and against tumor cell MUC1 after vaccination with MUC1-keyhole limpet hemocyanin (KLH) conjugate plus Qs-21 in breast cancer patients. Nine patients with a history of breast cancer but without evidence of disease were treated with MUC1-KLH conjugate plus Qs-21, containing 100μ g of MUC1 and 100 μg of Qs-21. s.c. vaccinations were administered at weeks 1, 2, 3, 7, and 19. Peripheral blood was drawn at frequent intervals to assess antibody titers. Skin tests were placed at weeks 1, 3, 9, and 21 to determine delayed type hypersensitivity reactions. Common toxicities included a local skin reaction at the site of the vaccine, usually of 4–5 days’ duration, and mild flu-like symptoms usually of 1–2 days’ duration. High IgM and IgG antibody titers against synthetic MUC1 were detected. IgG antibody titers remain elevated from a minimum of 106–137 weeks after the first vaccination. Binding of IgM antibody to MCF-7 tumor cells was observed in seven patients, although there was minimal binding of IgG antibody. Two patients developed significant antibody titers post-high-dose chemotherapy and stem cell reinfusion. There was no evidence of T cell activation. This MUC1-KLH conjugate plus Qs-21 was immunogenic and well tolerated in breast cancer patients. Additional trials are ongoing to determine the optimal MUC1 peptide for use in larger clinical trials. Further investigation of vaccine therapy in high-risk breast cancer is warranted.
Paul B Chapman - One of the best experts on this subject based on the ideXlab platform.
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consistent antibody response against ganglioside gd2 induced in patients with melanoma by a gd2 lactone keyhole limpet hemocyanin conjugate vaccine plus immunological adjuvant Qs 21
Clinical Cancer Research, 2003Co-Authors: Govind Ragupathi, Philip O Livingston, Linda Williams, Paul B Chapman, Chandra Hood, John Gathuru, Susan E Krown, Jedd D Wolchok, Roberta C OldfieldAbstract:Purpose: Melanomas, sarcomas, and neuroblastomas abundantly express the ganglioside GD2 on the cell surface where it is susceptible to immune attack by antibodies. Overexpression of GD2 on these tumors is striking, as is the frequency of clinical responses after treatment of neuroblastoma with monoclonal antibodies against GD2. In addition, preclinical models have demonstrated the ability of a GD2-keyhole limpet hemocyanin (KLH) conjugate vaccine to induce antibodies that eliminate micrometastases. However, vaccination of patients with GD2-KLH has previously failed to induce a consistent relevant antibody response. We test here whether the use of GD2 lactone-KLH can overcome the low immunogenicity of GD2-KLH. Experimental Design: Eighteen patients with melanoma were vaccinated s.c. in the adjuvant setting on weeks 0, 1, 2, 3, 10, and 24. Groups of 6 patients were entered at three dose levels (3, 10, or 30 μg) of GD2 lactone (GD2L) in vaccines containing GD2L-KLH plus the immunological adjuvant Qs-21. Blood was drawn at regular intervals to assess the antibody response. Results: The vaccine was well tolerated. The majority of patients in all three dose levels produced anti-GD2 antibodies detectable by ELISA assay. Specificity for GD2 was also confirmed by immune thin-layer chromatography. Although there was no statistical difference in terms of titers between the three groups, patients at the 30-μg dose level had higher titers and longer lasting antibody responses overall by ELISA (median IgM/IgG peak titer 1:640/1:80) and generated the strongest cell surface reactivity by fluorescence-activated cell sorting (median IgM peak percentage positive cells/mean fluorescence intensity for pre- and postvaccination sera is 10%/63 and 70%/135). Patients vaccinated with the 30-μg GD2 dose also had the most potent complement dependent cytotoxicity using human complement, with 5 of 6 patients showing strong cell surface reactivity by fluorescence-activated cell sorting and >30% cytotoxicity by chromium release with a serum dilution of 1/100. Conclusions: GD2L-KLH conjugate vaccine plus adjuvant Qs-21 induces antibodies against GD2 that bind to the cell surface and induce complement-dependent cytotoxicity in the majority of patients with melanoma.
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t cell responses against tyrosinase 368 376 370d peptide in hla a0201 melanoma patients randomized trial comparing incomplete freund s adjuvant granulocyte macrophage colony stimulating factor and Qs 21 as immunological adjuvants
Clinical Cancer Research, 2002Co-Authors: Susanne G. Schaed, Philip O Livingston, Katherine S Panageas, Alan N Houghton, Virginia M. Klimek, Cristina Musselli, Leah Butterworth, Linda Williams, Jonathan J. Lewis, Paul B ChapmanAbstract:We conducted a randomized trial in HLA∗A0201 + patientswith American Joint Committee on Cancer stage III or IV melanoma immunized with tyrosinase 368–376(370D) peptide and gp100 209–217(210M) peptide to compare the potency of three different adjuvants. Patients received 3 monthly immunizations with 500 μg of each peptide either with incomplete Freund’s adjuvant (IFA), Qs-21, or granulocyte macrophage colony-stimulating factor (GM-CSF). The primary end point was induction of IFN-γ release by CD8 + T cells against tyrosinase and gp100 peptides measured by enzyme-linked immunospot assays without in vitro prestimulation measured pretreatment, 2 and 8 weeks after the third vaccination. Four of 9 and 4 of 8 patients immunized using Qs-21 and GM-CSF, respectively, developed increased frequencies of CD8 + T cells against tyrosinase 370D peptide compared with 0 of 9 patients immunized using IFA ( P = 0.045). T-cell responses against a gp100-related peptide showed similar results, but their relevance to T-cell reactivity against native gp100 209–217 is uncertain. These results show that: ( a ) Qs-21 and GM-CSF are superior to IFA as immunological adjuvants for vaccination against tyrosinase 370D peptide; and ( b ) with appropriate adjuvants, increased frequencies of peptide-specific T cells after vaccination can be detected by enzyme-linked immunospot without prolonged prestimulation in vitro .
