Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma.
OBJECTIVE
The purpose of this study was to determine the toxicity and immunological effects of three different doses and two routes of administration of autologous dendritic cells (DCs) pulsed with the MART-1(27-35) immunodominant epitope.


METHODS
Eighteen HLA-A*0201-positive subjects with stage III-IV melanoma received three biweekly i.v. or intradermal injections of ex vivo generated myeloid DCs pulsed with MART-1(27-35) epitope. Repeated blood samples were processed to obtain peripheral blood mononuclear cells for immunological analysis using IFN-gamma ELISPOT, MHC class I tetramer, intracellular cytokine staining, and microcytotoxicity assays.


RESULTS
The frequency of MART-1/Melan-A (MART-1) antigen-specific T cells in peripheral blood increased in all dose levels as assessed by ELISPOT and MHC class I tetramer assays, but without a clear dose-response effect. The intradermal route generated stronger MART-1 immunity compared with the i.v. route. MART-1-specific immunity did not correlate with clinical outcome in any of the four immunological assays used. However, analysis of determinant spreading to other melanoma antigens was noted in the only subject with complete response to this single-epitope immunization.


CONCLUSIONS
Intradermal immunization with MART-1 peptide-pulsed DCs results in an increase in circulating IFN-gamma-producing, antigen-specific T cells. The frequency of these cells did not correlate with response. In contrast, spreading of immune reactivity to other melanoma antigens was only evident in a subject with a complete response, suggesting that determinant spreading may be an important factor of clinical response to this form of immunotherapy.
Butterfield
Lisa H
LH
Department of Surgery, Division of Surgical Oncology, UCLA Jonsson Comprehensive Cancer Center, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1782, USA.
Ribas
Antoni
A
Dissette
Vivian B
VB
Amarnani
Saral N
SN
Vu
Huong T
HT
Oseguera
Denise
D
Wang
He-Jing
HJ
Elashoff
Robert M
RM
McBride
William H
WH
Mukherji
Bijay
B
Cochran
Alistair J
AJ
Glaspy
John A
JA
Economou
James S
JS
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D016827:CD8 Antigens / Q000096:biosynthesis; D019496:Cancer Vaccines; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000737:chemistry / Q000627:therapeutic use*; D010452:Peptide Biosynthesis; D010455:Peptides / Q000737:chemistry; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D016827:CD8 Antigens; D019496:Cancer Vaccines; D016207:Cytokines; D000939:Epitopes; C105787:MART-1-Melan-A(27-35) epitope; D009363:Neoplasm Proteins; D010455:Peptides; D007371:Interferon-gamma