Immunization of patients with metastatic melanoma using both class i- and class ii-restricted peptides from melanoma-associated antigens

Giao Q. Phan, Christopher E. Touloukian, James C. Yang, Nicholas P. Restifo, Richard M. Sherry, Patrick Hwu, Suzanne L. Topalian, Douglas J. Schwartzentruber, Claudia A. Seipp, Linda J. Freezer, Kathleen E. Morton, Sharon A. Mavroukakis, Donald E. White, Steven A. Rosenberg

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer vaccines targeting CD8+ T cells have been successful in eliciting immunologic responses but disappointing in inducing clinical responses. Strong evidence supports the importance of CD4+ T cells in “helping” cytotoxic CD8+ cells in antitumor immunity. We report here on two consecutive clinical trials evaluating the impact of immunization with both human leukocyte antigen class I- and class II-restricted peptides from the gp100 melanoma antigen. In Protocol 1, 22 patients with metastatic melanoma were immunized with two modified class I A*0201-restricted peptides, gp100:209-217(210M) and MART-1:26-35(27L). In Protocol 2, 19 patients received the same class I-restricted peptides in combination with a class II DRB1*0401-restricted peptide, gp100:44-59. As assessed by in vitro sensitization assays using peripheral blood mononuclear cells (PBMC) against the native gp100:209-217 peptide, 95% of patients in Protocol 1 were successfully immunized after two vaccinations in contrast to 50% of patients in Protocol 2 (P2 < 0.005). Furthermore, the degree of sensitization was significantly lower in patients in Protocol 2 (P = 0.01). Clinically, one patient in Protocol 2 had an objective response, and none did in Protocol 1. Thus, the addition of the class II-restricted peptide gp100:44-59 did not improve clinical response but might have diminished the immunologic response of circulating PBMC to the class I-restricted peptide gp100:209-217. The reasons for this decreased immune reactivity are unclear but may involve increased CD4+CD25+ regulatory T-cell activity, increased apoptosis of activated CD8+ T cells, or the trafficking of sensitized CD8+ reactive cells out of the peripheral blood. Moreover, the sequential, nonrandomized nature of patient enrollment for the two trials may account for the differences in immunologic response.

Original languageEnglish (US)
Pages (from-to)349-356
Number of pages8
JournalJournal of Immunotherapy
Volume26
Issue number4
DOIs
StatePublished - 2003

Keywords

  • CD4 T cell
  • CD4CD25 T cell
  • CD8 T cell
  • Gp100
  • MART-1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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