Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy.
MART-1(27-35)-peptide-pulsed immature dendritic cells (DCs) resulted in immunologic and clinical activity in a prior phase 1 trial. A phase 2 cohort expansion was initiated to further characterize the phenotype and cytokine milieu of the DC vaccines and their immunologic activity in vitro and to further examine a possible link between clinical activity and determinant spreading. In an open-label phase 2 trial, 10(7) autologous ex vivo generated DCs pulsed with the HLA-A*0201 immunodominant peptide MART-1(27-35) were administered to 10 subjects with stage II-IV melanoma. The experimental vaccines were administered intradermally in a biweekly schedule for a total of three injections, and blood for immunologic assays was obtained before each administration and at three time points after. DC vaccine preparations had wide intra- and interpatient variability in terms of cell surface markers and preferential cytokine milieu, but they did not correlate with the levels of antigen-specific T cells after vaccination. Of four patients with measurable disease, one had stable disease for 6 months and another has a continued complete response for over 2 years, which is confounded by receiving a closely sequenced CTLA4 blocking antibody. The DC vaccines induced determinant spreading in this subject, and CTLA4 blockade reactivated T cells with prior antigen exposure. The DC phenotype and cytokine profile do not correlate with the ability to induce antigen-specific T cells, while determinant spreading after DC immunization may be a marker of an efficient antitumor response. Sequential CTLA4 blockade may enhance the immune activity of DC-based immunotherapy.
Department of Surgery, Division of Surgical Oncology, UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California, USA.
Antoni
A
Ribas
John A
JA
Glaspy
Yohan
Y
Lee
Vivian B
VB
Dissette
Elisabeth
E
Seja
Huong T
HT
Vu
N Simon
NS
Tchekmedyian
Denise
D
Oseguera
Begonya
B
Comin-Anduix
Jennifer A
JA
Wargo
Saral N
SN
Amarnani
William H
WH
McBride
James S
JS
Economou
Lisa H
LH
Butterfield
D000328:Adult; D000368:Aged; D019138:Antibodies, Blocking / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000627:therapeutic use; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007519:Isoantigens / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology*; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015415:Biomarkers; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D016207:Cytokines; D000939:Epitopes; D007519:Isoantigens; C415186:MART-1 antigen (27-35), Leu(28)-beta-HIle(30)-; D010446:Peptide Fragments