Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma

Steven A. Rosenberg, Richard M. Sherry, Kathleen E. Morton, William J. Scharfman, James C. Yang, Suzanne Topalian, Richard E. Royal, Udai Kammula, Nicholas P. Restifo, Marybeth S. Hughes, Douglas Schwartzentruber, David M. Berman, Susan L. Schwarz, Lien T. Ngo, Sharon A. Mavroukakis, Donald E. White, Seth M. Steinberg

Research output: Contribution to journalArticle

Abstract

The identification of many tumor-associated epitopes as nonmutated "self" Ags led to the hypothesis that the induction of large numbers of self/tumor Ag-specific T cells would be prevented because of central and peripheral tolerance. We report in this study on vaccination efforts in 95 HLA-A*0201 patients at high risk for recurrence of malignant melanoma who received prolonged immunization with the "anchor-modified" synthetic peptide, gp100209-217(210M). Vaccination using this altered peptide immunogen was highly effective at inducing large numbers of self/tumor-Ag reactive T cells in virtually every patient tested, with levels as high as 42% of all CD8+ T cells assessed by tetramer analysis. From 1 to 10% of all CD8+ cells were tumor-Ag reactive in 44% of patients and levels >10% were generated in 17% of patients. These studies were substantiated using the ELISPOT assay and a bulk cytokine release assay. Although our data regarding "tumor escape" were inconclusive, some patients had growing tumors that expressed Ag and HLA-A*0201 in the presence of high levels of antitumor T cells. There was no difference in the levels of antitumor Ag-specific T cells in patients who recurred compared with those that remained disease-free. Thus, the mere presence of profoundly expanded numbers of vaccine-induced, self/tumor Ag-specific T cells cannot by themselves be used as a "surrogate marker" for vaccine efficacy. Further, the induction of even high levels of antitumor T cells may be insufficient to alter tumor progression.

Original languageEnglish (US)
Pages (from-to)6169-6176
Number of pages8
JournalJournal of Immunology
Volume175
Issue number9
StatePublished - Nov 1 2005
Externally publishedYes

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Autoantigens
Neoplasm Antigens
Melanoma
T-Lymphocytes
Neoplasms
Vaccination
Marker Vaccines
Central Tolerance
Tumor Escape
Peripheral Tolerance
Enzyme-Linked Immunospot Assay
Peptides
Epitopes
Immunization
Vaccines
Biomarkers
Cytokines
Recurrence

ASJC Scopus subject areas

  • Immunology

Cite this

Rosenberg, S. A., Sherry, R. M., Morton, K. E., Scharfman, W. J., Yang, J. C., Topalian, S., ... Steinberg, S. M. (2005). Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. Journal of Immunology, 175(9), 6169-6176.

Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. / Rosenberg, Steven A.; Sherry, Richard M.; Morton, Kathleen E.; Scharfman, William J.; Yang, James C.; Topalian, Suzanne; Royal, Richard E.; Kammula, Udai; Restifo, Nicholas P.; Hughes, Marybeth S.; Schwartzentruber, Douglas; Berman, David M.; Schwarz, Susan L.; Ngo, Lien T.; Mavroukakis, Sharon A.; White, Donald E.; Steinberg, Seth M.

In: Journal of Immunology, Vol. 175, No. 9, 01.11.2005, p. 6169-6176.

Research output: Contribution to journalArticle

Rosenberg, SA, Sherry, RM, Morton, KE, Scharfman, WJ, Yang, JC, Topalian, S, Royal, RE, Kammula, U, Restifo, NP, Hughes, MS, Schwartzentruber, D, Berman, DM, Schwarz, SL, Ngo, LT, Mavroukakis, SA, White, DE & Steinberg, SM 2005, 'Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma', Journal of Immunology, vol. 175, no. 9, pp. 6169-6176.
Rosenberg, Steven A. ; Sherry, Richard M. ; Morton, Kathleen E. ; Scharfman, William J. ; Yang, James C. ; Topalian, Suzanne ; Royal, Richard E. ; Kammula, Udai ; Restifo, Nicholas P. ; Hughes, Marybeth S. ; Schwartzentruber, Douglas ; Berman, David M. ; Schwarz, Susan L. ; Ngo, Lien T. ; Mavroukakis, Sharon A. ; White, Donald E. ; Steinberg, Seth M. / Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. In: Journal of Immunology. 2005 ; Vol. 175, No. 9. pp. 6169-6176.
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abstract = "The identification of many tumor-associated epitopes as nonmutated {"}self{"} Ags led to the hypothesis that the induction of large numbers of self/tumor Ag-specific T cells would be prevented because of central and peripheral tolerance. We report in this study on vaccination efforts in 95 HLA-A*0201 patients at high risk for recurrence of malignant melanoma who received prolonged immunization with the {"}anchor-modified{"} synthetic peptide, gp100209-217(210M). Vaccination using this altered peptide immunogen was highly effective at inducing large numbers of self/tumor-Ag reactive T cells in virtually every patient tested, with levels as high as 42{\%} of all CD8+ T cells assessed by tetramer analysis. From 1 to 10{\%} of all CD8+ cells were tumor-Ag reactive in 44{\%} of patients and levels >10{\%} were generated in 17{\%} of patients. These studies were substantiated using the ELISPOT assay and a bulk cytokine release assay. Although our data regarding {"}tumor escape{"} were inconclusive, some patients had growing tumors that expressed Ag and HLA-A*0201 in the presence of high levels of antitumor T cells. There was no difference in the levels of antitumor Ag-specific T cells in patients who recurred compared with those that remained disease-free. Thus, the mere presence of profoundly expanded numbers of vaccine-induced, self/tumor Ag-specific T cells cannot by themselves be used as a {"}surrogate marker{"} for vaccine efficacy. Further, the induction of even high levels of antitumor T cells may be insufficient to alter tumor progression.",
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AU - Rosenberg, Steven A.

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AU - Morton, Kathleen E.

AU - Scharfman, William J.

AU - Yang, James C.

AU - Topalian, Suzanne

AU - Royal, Richard E.

AU - Kammula, Udai

AU - Restifo, Nicholas P.

AU - Hughes, Marybeth S.

AU - Schwartzentruber, Douglas

AU - Berman, David M.

AU - Schwarz, Susan L.

AU - Ngo, Lien T.

AU - Mavroukakis, Sharon A.

AU - White, Donald E.

AU - Steinberg, Seth M.

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