Immunization of patients with metastatic melanoma using both class I- and class II-restricted peptides from melanoma-associated antigens.
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 (P(2) < 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.
Phan
Giao Q
GQ
Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892-1502, USA.
Touloukian
Christopher E
CE
Yang
James C
JC
Restifo
Nicholas P
NP
Sherry
Richard M
RM
Hwu
Patrick
P
Topalian
Suzanne L
SL
Schwartzentruber
Douglas J
DJ
Seipp
Claudia A
CA
Freezer
Linda J
LJ
Morton
Kathleen E
KE
Mavroukakis
Sharon A
SA
White
Donald E
DE
Rosenberg
Steven A
SA
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines; D002986:Clinical Trials as Topic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000737:chemistry* / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000737:chemistry; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology; D010455:Peptides / Q000737:chemistry; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016896:Treatment Outcome; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D007376:Interleukin-2; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010455:Peptides; D015375:Receptors, Interleukin-2; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma