TY - JOUR
T1 - Immunization of patients with metastatic melanoma using both class i- and class ii-restricted peptides from melanoma-associated antigens
AU - Phan, Giao Q.
AU - Touloukian, Christopher E.
AU - Yang, James C.
AU - Restifo, Nicholas P.
AU - Sherry, Richard M.
AU - Hwu, Patrick
AU - Topalian, Suzanne L.
AU - Schwartzentruber, Douglas J.
AU - Seipp, Claudia A.
AU - Freezer, Linda J.
AU - Morton, Kathleen E.
AU - Mavroukakis, Sharon A.
AU - White, Donald E.
AU - Rosenberg, Steven A.
PY - 2003
Y1 - 2003
N2 - 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.
AB - 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.
KW - CD4 T cell
KW - CD4CD25 T cell
KW - CD8 T cell
KW - Gp100
KW - MART-1
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UR - http://www.scopus.com/inward/citedby.url?scp=10744222813&partnerID=8YFLogxK
U2 - 10.1097/00002371-200307000-00007
DO - 10.1097/00002371-200307000-00007
M3 - Article
C2 - 12843797
AN - SCOPUS:10744222813
SN - 1524-9557
VL - 26
SP - 349
EP - 356
JO - Journal of Immunotherapy
JF - Journal of Immunotherapy
IS - 4
ER -