Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanoma

Evidence of systemic immune dysfunction

Esteban Celis, Svetomir N. Markovic, Vera J. Suman, Ravi D. Rao, Edward T. Creagan, Keith L. Knutson, Alexey A. Leontovich, James N. Ingle, Judith S. Kaur, Lori A. Erickson, Henry C. Pitot, Jacob B. Allred, Lisa A. Kottschade, Robert R. McWilliams, Gary A. Croghan, Wendy K. Nevala

Research output: Contribution to journalArticle

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Abstract

BACKGROUND. MPS160 (GRAMLGTHTMEVTV) is a glycoprotein 100-derived melanoma peptide that contains overlapping human leukemic antigen A2-, DR53-, and DQw6-restricted T-cell epitopes. In preclinical testing, MPS160 demonstrated superior immunization and antitumor activity. In this report, the authors present the results from a clinical trial that evaluated the safety and immunologic efficacy of the MPS 160 vaccine in patients with metastatic melanoma. METHODS. Patients with stage IV melanoma were randomized to 1 of 3 treatment arms: 1) MPS160 in incomplete Freund adjuvant (Montanide ISA-51); 2) MPS160 in Montanide ISA-51 with 75 ng of granulocyte-macrophage-stimulating factor (GM-CSF); or 3) MPS160 in Montanide ISA-51 with 100 ng of GM-CSF. Vaccines were administered every 3 weeks until patients developed disease progression or severe toxicity. Patients were aged ≥18 years with metastatic melanoma and a good performance status. Exclusion criteria included pregnancy/nursing, brain metastases, and ongoing chemotherapy. Immunologic efficacy was ascertained by using tetramer and functional analysis of peripheral blood lymphocytes. RESULTS. None of the 28 patients exhibited objective tumor responses or severe toxicities. Four patients remained progression free for ≥100 days. Immunologic analysis was available for 21 patients. Laboratory data demonstrated 1) increased frequency of vaccine-specific, nonfunctional cytotoxic T lymphocytes in 10 patients; 2) no differences in immunization efficacy among the treatment arms; and 3) evidence of systemic cytokine/immune dysfunction. CONCLUSIONS. Clinically, the MPS160 vaccine was ineffective. Phenotypic (tetramer) evidence of immunization was ineffective functionally and most likely was caused by global immune dysfunction, as illustrated by abnormal cytokine profiles in peripheral blood. In this report, the authors discuss possible implications of the current results on future cancer vaccine studies.

Original languageEnglish (US)
Pages (from-to)203-214
Number of pages12
JournalCancer
Volume110
Issue number1
DOIs
StatePublished - Jul 1 2007

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Subunit Vaccines
HLA Antigens
Melanoma
Vaccines
Immunization
Therapeutics
Granulocytes
Macrophages
Cytokines
Cancer Vaccines
T-Lymphocyte Epitopes
Cytotoxic T-Lymphocytes
GRAMLGTHTMEVTV
varespladib methyl
Disease Progression
Glycoproteins
Nursing
Clinical Trials
Lymphocytes
Neoplasm Metastasis

Keywords

  • Cytokines
  • Granulocyte-macrophage-stimulating factor
  • Melanoma
  • Peptide
  • Vaccine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanoma : Evidence of systemic immune dysfunction. / Celis, Esteban; Markovic, Svetomir N.; Suman, Vera J.; Rao, Ravi D.; Creagan, Edward T.; Knutson, Keith L.; Leontovich, Alexey A.; Ingle, James N.; Kaur, Judith S.; Erickson, Lori A.; Pitot, Henry C.; Allred, Jacob B.; Kottschade, Lisa A.; McWilliams, Robert R.; Croghan, Gary A.; Nevala, Wendy K.

In: Cancer, Vol. 110, No. 1, 01.07.2007, p. 203-214.

Research output: Contribution to journalArticle

Celis, E, Markovic, SN, Suman, VJ, Rao, RD, Creagan, ET, Knutson, KL, Leontovich, AA, Ingle, JN, Kaur, JS, Erickson, LA, Pitot, HC, Allred, JB, Kottschade, LA, McWilliams, RR, Croghan, GA & Nevala, WK 2007, 'Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanoma: Evidence of systemic immune dysfunction', Cancer, vol. 110, no. 1, pp. 203-214. https://doi.org/10.1002/cncr.22744
Celis, Esteban ; Markovic, Svetomir N. ; Suman, Vera J. ; Rao, Ravi D. ; Creagan, Edward T. ; Knutson, Keith L. ; Leontovich, Alexey A. ; Ingle, James N. ; Kaur, Judith S. ; Erickson, Lori A. ; Pitot, Henry C. ; Allred, Jacob B. ; Kottschade, Lisa A. ; McWilliams, Robert R. ; Croghan, Gary A. ; Nevala, Wendy K. / Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanoma : Evidence of systemic immune dysfunction. In: Cancer. 2007 ; Vol. 110, No. 1. pp. 203-214.
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abstract = "BACKGROUND. MPS160 (GRAMLGTHTMEVTV) is a glycoprotein 100-derived melanoma peptide that contains overlapping human leukemic antigen A2-, DR53-, and DQw6-restricted T-cell epitopes. In preclinical testing, MPS160 demonstrated superior immunization and antitumor activity. In this report, the authors present the results from a clinical trial that evaluated the safety and immunologic efficacy of the MPS 160 vaccine in patients with metastatic melanoma. METHODS. Patients with stage IV melanoma were randomized to 1 of 3 treatment arms: 1) MPS160 in incomplete Freund adjuvant (Montanide ISA-51); 2) MPS160 in Montanide ISA-51 with 75 ng of granulocyte-macrophage-stimulating factor (GM-CSF); or 3) MPS160 in Montanide ISA-51 with 100 ng of GM-CSF. Vaccines were administered every 3 weeks until patients developed disease progression or severe toxicity. Patients were aged ≥18 years with metastatic melanoma and a good performance status. Exclusion criteria included pregnancy/nursing, brain metastases, and ongoing chemotherapy. Immunologic efficacy was ascertained by using tetramer and functional analysis of peripheral blood lymphocytes. RESULTS. None of the 28 patients exhibited objective tumor responses or severe toxicities. Four patients remained progression free for ≥100 days. Immunologic analysis was available for 21 patients. Laboratory data demonstrated 1) increased frequency of vaccine-specific, nonfunctional cytotoxic T lymphocytes in 10 patients; 2) no differences in immunization efficacy among the treatment arms; and 3) evidence of systemic cytokine/immune dysfunction. CONCLUSIONS. Clinically, the MPS160 vaccine was ineffective. Phenotypic (tetramer) evidence of immunization was ineffective functionally and most likely was caused by global immune dysfunction, as illustrated by abnormal cytokine profiles in peripheral blood. In this report, the authors discuss possible implications of the current results on future cancer vaccine studies.",
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T1 - Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanoma

T2 - Evidence of systemic immune dysfunction

AU - Celis, Esteban

AU - Markovic, Svetomir N.

AU - Suman, Vera J.

AU - Rao, Ravi D.

AU - Creagan, Edward T.

AU - Knutson, Keith L.

AU - Leontovich, Alexey A.

AU - Ingle, James N.

AU - Kaur, Judith S.

AU - Erickson, Lori A.

AU - Pitot, Henry C.

AU - Allred, Jacob B.

AU - Kottschade, Lisa A.

AU - McWilliams, Robert R.

AU - Croghan, Gary A.

AU - Nevala, Wendy K.

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N2 - BACKGROUND. MPS160 (GRAMLGTHTMEVTV) is a glycoprotein 100-derived melanoma peptide that contains overlapping human leukemic antigen A2-, DR53-, and DQw6-restricted T-cell epitopes. In preclinical testing, MPS160 demonstrated superior immunization and antitumor activity. In this report, the authors present the results from a clinical trial that evaluated the safety and immunologic efficacy of the MPS 160 vaccine in patients with metastatic melanoma. METHODS. Patients with stage IV melanoma were randomized to 1 of 3 treatment arms: 1) MPS160 in incomplete Freund adjuvant (Montanide ISA-51); 2) MPS160 in Montanide ISA-51 with 75 ng of granulocyte-macrophage-stimulating factor (GM-CSF); or 3) MPS160 in Montanide ISA-51 with 100 ng of GM-CSF. Vaccines were administered every 3 weeks until patients developed disease progression or severe toxicity. Patients were aged ≥18 years with metastatic melanoma and a good performance status. Exclusion criteria included pregnancy/nursing, brain metastases, and ongoing chemotherapy. Immunologic efficacy was ascertained by using tetramer and functional analysis of peripheral blood lymphocytes. RESULTS. None of the 28 patients exhibited objective tumor responses or severe toxicities. Four patients remained progression free for ≥100 days. Immunologic analysis was available for 21 patients. Laboratory data demonstrated 1) increased frequency of vaccine-specific, nonfunctional cytotoxic T lymphocytes in 10 patients; 2) no differences in immunization efficacy among the treatment arms; and 3) evidence of systemic cytokine/immune dysfunction. CONCLUSIONS. Clinically, the MPS160 vaccine was ineffective. Phenotypic (tetramer) evidence of immunization was ineffective functionally and most likely was caused by global immune dysfunction, as illustrated by abnormal cytokine profiles in peripheral blood. In this report, the authors discuss possible implications of the current results on future cancer vaccine studies.

AB - BACKGROUND. MPS160 (GRAMLGTHTMEVTV) is a glycoprotein 100-derived melanoma peptide that contains overlapping human leukemic antigen A2-, DR53-, and DQw6-restricted T-cell epitopes. In preclinical testing, MPS160 demonstrated superior immunization and antitumor activity. In this report, the authors present the results from a clinical trial that evaluated the safety and immunologic efficacy of the MPS 160 vaccine in patients with metastatic melanoma. METHODS. Patients with stage IV melanoma were randomized to 1 of 3 treatment arms: 1) MPS160 in incomplete Freund adjuvant (Montanide ISA-51); 2) MPS160 in Montanide ISA-51 with 75 ng of granulocyte-macrophage-stimulating factor (GM-CSF); or 3) MPS160 in Montanide ISA-51 with 100 ng of GM-CSF. Vaccines were administered every 3 weeks until patients developed disease progression or severe toxicity. Patients were aged ≥18 years with metastatic melanoma and a good performance status. Exclusion criteria included pregnancy/nursing, brain metastases, and ongoing chemotherapy. Immunologic efficacy was ascertained by using tetramer and functional analysis of peripheral blood lymphocytes. RESULTS. None of the 28 patients exhibited objective tumor responses or severe toxicities. Four patients remained progression free for ≥100 days. Immunologic analysis was available for 21 patients. Laboratory data demonstrated 1) increased frequency of vaccine-specific, nonfunctional cytotoxic T lymphocytes in 10 patients; 2) no differences in immunization efficacy among the treatment arms; and 3) evidence of systemic cytokine/immune dysfunction. CONCLUSIONS. Clinically, the MPS160 vaccine was ineffective. Phenotypic (tetramer) evidence of immunization was ineffective functionally and most likely was caused by global immune dysfunction, as illustrated by abnormal cytokine profiles in peripheral blood. In this report, the authors discuss possible implications of the current results on future cancer vaccine studies.

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