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A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission

We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological...

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Autores principales: O’Cearbhaill, Roisin E., Ragupathi, Govind, Zhu, Jianglong, Wan, Qian, Mironov, Svetlana, Yang, Guangbin, Spassova, Maria K., Iasonos, Alexia, Kravetz, Sara, Ouerfelli, Ouathek, Spriggs, David R., Danishefsky, Samuel J., Sabbatini, Paul J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846855/
https://www.ncbi.nlm.nih.gov/pubmed/27110823
http://dx.doi.org/10.3390/cancers8040046
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author O’Cearbhaill, Roisin E.
Ragupathi, Govind
Zhu, Jianglong
Wan, Qian
Mironov, Svetlana
Yang, Guangbin
Spassova, Maria K.
Iasonos, Alexia
Kravetz, Sara
Ouerfelli, Ouathek
Spriggs, David R.
Danishefsky, Samuel J.
Sabbatini, Paul J.
author_facet O’Cearbhaill, Roisin E.
Ragupathi, Govind
Zhu, Jianglong
Wan, Qian
Mironov, Svetlana
Yang, Guangbin
Spassova, Maria K.
Iasonos, Alexia
Kravetz, Sara
Ouerfelli, Ouathek
Spriggs, David R.
Danishefsky, Samuel J.
Sabbatini, Paul J.
author_sort O’Cearbhaill, Roisin E.
collection PubMed
description We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011–Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient’s pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36–68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2–39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability.
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spelling pubmed-48468552016-05-04 A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission O’Cearbhaill, Roisin E. Ragupathi, Govind Zhu, Jianglong Wan, Qian Mironov, Svetlana Yang, Guangbin Spassova, Maria K. Iasonos, Alexia Kravetz, Sara Ouerfelli, Ouathek Spriggs, David R. Danishefsky, Samuel J. Sabbatini, Paul J. Cancers (Basel) Article We conducted a phase I study in ovarian cancer patients to evaluate the safety and immunogenicity of a synthetic unimolecular pentavalent carbohydrate vaccine (Globo-H, GM2, sTn, TF, and Tn) supported on a peptide backbone, conjugated to keyhole limpet haemocyanin (KLH), and mixed with immunological adjuvant QS-21. Twenty-four advanced-stage, poor-risk, first-remission ovarian cancer patients were enrolled from January 2011–Septermber 2013. Three dose levels were planned (25, 50, 100 mcg) with three cohorts of six patients each, with an additional 6-patient expansion cohort at the MTD. ELISA serologic IgM and IgG responses for each antigen was defined as positive response if antibody titers were ≥1:80 over the respective patient’s pre-vaccination serum. The study would be considered positive if at least four of 12 patients treated at the MTD showed immune responses for at least three of the five antigens. Twenty-four patients (median age, 54 years [range, 36–68]) were included in the safety analysis. Histology was high-grade serous in 22 patients (92%); 18 had stage III and six stage IV disease. The vaccine was well-tolerated at all doses, with no DLTs. At the highest treated dose, IgG and/or IgM responses were recorded against ≥3 antigens in 9/12 patients (75%), ≥4 in 7/12 (58%), and 5 in 3/12 (25%). With a median follow-up of 19 months (range, 2–39), 20 patients (83%) recurred and six (25%) died. The unimolecular pentavalent vaccine construct was shown to be safe and immunogenic. Such a construct greatly simplifies regulatory requirements and manufacturing, facilitates scalability, and provides adaptability. MDPI 2016-04-22 /pmc/articles/PMC4846855/ /pubmed/27110823 http://dx.doi.org/10.3390/cancers8040046 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
O’Cearbhaill, Roisin E.
Ragupathi, Govind
Zhu, Jianglong
Wan, Qian
Mironov, Svetlana
Yang, Guangbin
Spassova, Maria K.
Iasonos, Alexia
Kravetz, Sara
Ouerfelli, Ouathek
Spriggs, David R.
Danishefsky, Samuel J.
Sabbatini, Paul J.
A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission
title A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission
title_full A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission
title_fullStr A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission
title_full_unstemmed A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission
title_short A Phase I Study of Unimolecular Pentavalent (Globo-H-GM2-sTn-TF-Tn) Immunization of Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer in First Remission
title_sort phase i study of unimolecular pentavalent (globo-h-gm2-stn-tf-tn) immunization of patients with epithelial ovarian, fallopian tube, or peritoneal cancer in first remission
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846855/
https://www.ncbi.nlm.nih.gov/pubmed/27110823
http://dx.doi.org/10.3390/cancers8040046
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