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HLA-Independent Heterogeneity of CD8⁺ T Cell Responses to MAGE-3, Melan-A/MART-1, gp100, Tyrosinase, MC1R, and TRP-2 in Vaccine-Treated Melanoma Patients¹

Sandra R. Reynolds^*, Esteban Celis^2,§, Alessandro Sette^§, Ruth Oratz, Richard L. Shapiro, Dean Johnston^*, Marilena Fotino^¶ and Jean-Claude Bystryn^3,*

^* Ronald O. Perelman Department of Dermatology, Departments of Medicine and Surgery, New York University Medical Center, New York, NY 10016; ^§ Epimmune, Inc., San Diego, CA 92121; and ^¶ The Rogosin Institute, New York, NY 10021

An important element in melanoma vaccine construction is to identify peptides from melanoma-associated Ags that have immunogenic potential in humans and are recognized by CD8⁺ T cells in vivo. To identify such peptides, we evaluated HLA-A*02⁺ melanoma patients immunized to a polyvalent vaccine containing multiple Ags, including MAGE-3, Melan-A/MART-1, gp100, tyrosinase, melanocortin receptor (MC1R), and dopachrome tautomerase (TRP-2). Using a filter spot assay, we measured peripheral blood CD8⁺ T cell responses, before and after immunization, to a panel of 45 HLA-A*0201-restricted peptides derived from these Ags. The peptides were selected for immunogenic potential based on their strong binding affinity in vitro to HLA-A*0201. Vaccine treatment induced peptide-specific CD8⁺ T cell responses to 22 (47.8%) of the peptides. The most striking finding was the HLA-independent heterogeneity of responses to both peptides and Ags. All responding patients reacted to different combination of peptides and Ags even though the responding patients were all A*0201⁺ and the peptides were all A*0201-restricted. From 9 to 27% of patients developed a CD8⁺ T cell response to at least one peptide from each Ag, but no more than 3 (14%) reacted to the same peptide from the same Ag. This heterogeneity of responses to individual peptides and Ags in patients with the same haplotype points to the need to construct vaccines of multiple peptides or Ags to maximize the proportion of responding patients.

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