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Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma

BACKGROUND: Glycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96) can elicit potent tumor-specific T cell responses and protective immunity in animal models. We sought to investigate th...

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Autores principales: Eton, Omar, Ross, Merrick I, East, Mary Jo, Mansfield, Paul F, Papadopoulos, Nicholas, Ellerhorst, Julie A, Bedikian, Agop Y, Lee, Jeffrey E
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835652/
https://www.ncbi.nlm.nih.gov/pubmed/20109236
http://dx.doi.org/10.1186/1479-5876-8-9
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author Eton, Omar
Ross, Merrick I
East, Mary Jo
Mansfield, Paul F
Papadopoulos, Nicholas
Ellerhorst, Julie A
Bedikian, Agop Y
Lee, Jeffrey E
author_facet Eton, Omar
Ross, Merrick I
East, Mary Jo
Mansfield, Paul F
Papadopoulos, Nicholas
Ellerhorst, Julie A
Bedikian, Agop Y
Lee, Jeffrey E
author_sort Eton, Omar
collection PubMed
description BACKGROUND: Glycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96) can elicit potent tumor-specific T cell responses and protective immunity in animal models. We sought to investigate the feasibility, safety, and antitumor activity of HSPPC-96 vaccines prepared from tumor specimens of patients with metastatic melanoma. METHODS: Patients with a Karnofsky Performance Status >70% and stage III or stage IV melanoma had to have a metastasis >3 cm in diameter resectable as part of routine clinical management. HSPPC-96 tumor-derived vaccines were prepared in one of three dose levels (2.5, 25, or 100 μg/dose) and administered as an intradermal injection weekly for 4 consecutive weeks. In vivo induction of immunity was evaluated using delayed-type hypersensitivity (DTH) to HSPPC-96, irradiated tumor, and dinitrochlorobenzene (DNCB). The γ-interferon (IFNγ) ELISPOT assay was used to measure induction of a peripheral blood mononuclear cell response against autologous tumor cells at baseline and at the beginning of weeks 3, 4, and 8. RESULTS: Among 36 patients enrolled, 72% had stage IV melanoma and 83% had received prior systemic therapy. The smallest tumor specimen from which HSPPC-96 was prepared weighed 2 g. Twelve patients (including 9 with stage IV and indicator lesions) had a negative DNCB skin test result at baseline. All 36 patients were treated and evaluable for toxicity and response. There were no serious toxicities. There were no observed DTH responses to HSPPC-96 or to autologous tumor cells before or during treatment. The IFNγ-producing cell count rose modestly in 5 of 26 patients and returned to baseline by week 8, with no discernible association with HSPPC-96 dosing or clinical parameters. There were no objective responses among 16 patients with stage IV disease and indicator lesions. Among 20 patients treated in the adjuvant setting, 11 with stage IV melanoma at baseline had a progression-free and overall survival of 45% and 82%, respectively, with a median follow-up of 10 years. CONCLUSION: Treatment with autologous tumor-derived HSPPC-96 was feasible and safe at all doses tested. Observed immunological effects and antitumor activity were modest, precluding selection of a biologically active dose. Nevertheless, the 25-μg dose level was shown to be practical for further study.
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spelling pubmed-28356522010-03-10 Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma Eton, Omar Ross, Merrick I East, Mary Jo Mansfield, Paul F Papadopoulos, Nicholas Ellerhorst, Julie A Bedikian, Agop Y Lee, Jeffrey E J Transl Med Research BACKGROUND: Glycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96) can elicit potent tumor-specific T cell responses and protective immunity in animal models. We sought to investigate the feasibility, safety, and antitumor activity of HSPPC-96 vaccines prepared from tumor specimens of patients with metastatic melanoma. METHODS: Patients with a Karnofsky Performance Status >70% and stage III or stage IV melanoma had to have a metastasis >3 cm in diameter resectable as part of routine clinical management. HSPPC-96 tumor-derived vaccines were prepared in one of three dose levels (2.5, 25, or 100 μg/dose) and administered as an intradermal injection weekly for 4 consecutive weeks. In vivo induction of immunity was evaluated using delayed-type hypersensitivity (DTH) to HSPPC-96, irradiated tumor, and dinitrochlorobenzene (DNCB). The γ-interferon (IFNγ) ELISPOT assay was used to measure induction of a peripheral blood mononuclear cell response against autologous tumor cells at baseline and at the beginning of weeks 3, 4, and 8. RESULTS: Among 36 patients enrolled, 72% had stage IV melanoma and 83% had received prior systemic therapy. The smallest tumor specimen from which HSPPC-96 was prepared weighed 2 g. Twelve patients (including 9 with stage IV and indicator lesions) had a negative DNCB skin test result at baseline. All 36 patients were treated and evaluable for toxicity and response. There were no serious toxicities. There were no observed DTH responses to HSPPC-96 or to autologous tumor cells before or during treatment. The IFNγ-producing cell count rose modestly in 5 of 26 patients and returned to baseline by week 8, with no discernible association with HSPPC-96 dosing or clinical parameters. There were no objective responses among 16 patients with stage IV disease and indicator lesions. Among 20 patients treated in the adjuvant setting, 11 with stage IV melanoma at baseline had a progression-free and overall survival of 45% and 82%, respectively, with a median follow-up of 10 years. CONCLUSION: Treatment with autologous tumor-derived HSPPC-96 was feasible and safe at all doses tested. Observed immunological effects and antitumor activity were modest, precluding selection of a biologically active dose. Nevertheless, the 25-μg dose level was shown to be practical for further study. BioMed Central 2010-01-29 /pmc/articles/PMC2835652/ /pubmed/20109236 http://dx.doi.org/10.1186/1479-5876-8-9 Text en Copyright ©2010 Eton et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Eton, Omar
Ross, Merrick I
East, Mary Jo
Mansfield, Paul F
Papadopoulos, Nicholas
Ellerhorst, Julie A
Bedikian, Agop Y
Lee, Jeffrey E
Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma
title Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma
title_full Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma
title_fullStr Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma
title_full_unstemmed Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma
title_short Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma
title_sort autologous tumor-derived heat-shock protein peptide complex-96 (hsppc-96) in patients with metastatic melanoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835652/
https://www.ncbi.nlm.nih.gov/pubmed/20109236
http://dx.doi.org/10.1186/1479-5876-8-9
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