Melanoma immunotherapy using mature DCs expressing the constitutive proteasome

Jens Dannull, N. Rebecca Haley, Gary Archer, Smita Nair, David Boczkowski, Mark Harper, Nicole De Rosa, Nancy Pickett, Paul J. Mosca, James Burchette, Maria A. Selim, Duane A. Mitchell, John Sampson, Douglas Tyler, Scott K. Pruitt

Research output: Contribution to journalArticle

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Abstract

Background. Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen-loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo. Methods. Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5). Results. Vaccination stimulated antigen-specific T cell responses in all subjects, which peaked after 3-4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2+ subjects, CD8+ T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response. Conclusion. These results suggest that the efficacy of melanoma DC-based immunotherapy is enhanced when tumor antigen-loaded DCs used for vaccination express cPs. Trial registration. Clinicaltrials.gov NCT00672542.

Original languageEnglish (US)
Pages (from-to)3135-3145
Number of pages11
JournalJournal of Clinical Investigation
Volume123
Issue number7
DOIs
StatePublished - Jul 1 2013
Externally publishedYes

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Proteasome Endopeptidase Complex
Immunotherapy
Melanoma
Melanoma-Specific Antigens
Vaccination
T-Lymphocytes
HLA-A2 Antigen
Antigens
Peptides
Monophenol Monooxygenase
Neoplasm Antigens
Small Interfering RNA
Monocytes
Immunity
RNA
Neoplasm Metastasis
Polymerase Chain Reaction
Skin
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dannull, J., Haley, N. R., Archer, G., Nair, S., Boczkowski, D., Harper, M., ... Pruitt, S. K. (2013). Melanoma immunotherapy using mature DCs expressing the constitutive proteasome. Journal of Clinical Investigation, 123(7), 3135-3145. https://doi.org/10.1172/JCI67544

Melanoma immunotherapy using mature DCs expressing the constitutive proteasome. / Dannull, Jens; Haley, N. Rebecca; Archer, Gary; Nair, Smita; Boczkowski, David; Harper, Mark; De Rosa, Nicole; Pickett, Nancy; Mosca, Paul J.; Burchette, James; Selim, Maria A.; Mitchell, Duane A.; Sampson, John; Tyler, Douglas; Pruitt, Scott K.

In: Journal of Clinical Investigation, Vol. 123, No. 7, 01.07.2013, p. 3135-3145.

Research output: Contribution to journalArticle

Dannull, J, Haley, NR, Archer, G, Nair, S, Boczkowski, D, Harper, M, De Rosa, N, Pickett, N, Mosca, PJ, Burchette, J, Selim, MA, Mitchell, DA, Sampson, J, Tyler, D & Pruitt, SK 2013, 'Melanoma immunotherapy using mature DCs expressing the constitutive proteasome', Journal of Clinical Investigation, vol. 123, no. 7, pp. 3135-3145. https://doi.org/10.1172/JCI67544
Dannull J, Haley NR, Archer G, Nair S, Boczkowski D, Harper M et al. Melanoma immunotherapy using mature DCs expressing the constitutive proteasome. Journal of Clinical Investigation. 2013 Jul 1;123(7):3135-3145. https://doi.org/10.1172/JCI67544
Dannull, Jens ; Haley, N. Rebecca ; Archer, Gary ; Nair, Smita ; Boczkowski, David ; Harper, Mark ; De Rosa, Nicole ; Pickett, Nancy ; Mosca, Paul J. ; Burchette, James ; Selim, Maria A. ; Mitchell, Duane A. ; Sampson, John ; Tyler, Douglas ; Pruitt, Scott K. / Melanoma immunotherapy using mature DCs expressing the constitutive proteasome. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 7. pp. 3135-3145.
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abstract = "Background. Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen-loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo. Methods. Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5). Results. Vaccination stimulated antigen-specific T cell responses in all subjects, which peaked after 3-4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2+ subjects, CD8+ T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response. Conclusion. These results suggest that the efficacy of melanoma DC-based immunotherapy is enhanced when tumor antigen-loaded DCs used for vaccination express cPs. Trial registration. Clinicaltrials.gov NCT00672542.",
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AU - Dannull, Jens

AU - Haley, N. Rebecca

AU - Archer, Gary

AU - Nair, Smita

AU - Boczkowski, David

AU - Harper, Mark

AU - De Rosa, Nicole

AU - Pickett, Nancy

AU - Mosca, Paul J.

AU - Burchette, James

AU - Selim, Maria A.

AU - Mitchell, Duane A.

AU - Sampson, John

AU - Tyler, Douglas

AU - Pruitt, Scott K.

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N2 - Background. Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen-loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo. Methods. Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5). Results. Vaccination stimulated antigen-specific T cell responses in all subjects, which peaked after 3-4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2+ subjects, CD8+ T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response. Conclusion. These results suggest that the efficacy of melanoma DC-based immunotherapy is enhanced when tumor antigen-loaded DCs used for vaccination express cPs. Trial registration. Clinicaltrials.gov NCT00672542.

AB - Background. Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen-loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo. Methods. Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5). Results. Vaccination stimulated antigen-specific T cell responses in all subjects, which peaked after 3-4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2+ subjects, CD8+ T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response. Conclusion. These results suggest that the efficacy of melanoma DC-based immunotherapy is enhanced when tumor antigen-loaded DCs used for vaccination express cPs. Trial registration. Clinicaltrials.gov NCT00672542.

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