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

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.

• Authors: Steven A Rosenberg, Richard M Sherry, Kathleen E Morton, William J Scharfman, James C Yang, Suzanne L 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
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 175 Issue 9 Pg. 6169-76 (Nov 01 2005) ISSN: 0022-1767 [Print] United States
• PMID: 16237114 (Publication Type: Journal Article)

Chemical References

• Antigens, Neoplasm
• Autoantigens
• Cancer Vaccines
• Membrane Glycoproteins
• PMEL protein, human
• Peptide Fragments
• gp100 Melanoma Antigen

Topics

• Adult
• Aged
• Antigens, Neoplasm (immunology)
• Autoantigens (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (immunology)
• Disease Progression
• Female
• Humans
• Immunization
• Male
• Melanoma (immunology, mortality, therapy)
• Membrane Glycoproteins (immunology)
• Middle Aged
• Peptide Fragments (immunology)
• Skin Neoplasms (immunology, mortality, therapy)
• gp100 Melanoma Antigen