Vaccination with mRNA-electroporated dendritic cells induces robust tumor antigen-specific CD4+ and CD8+ T cells responses in stage III and IV melanoma patients.
OBJECTIVE
Electroporation of dendritic cells (DC) with mRNA encoding tumor-associated antigens (TAA) has multiple advantages compared to peptide loading. We investigated the immunologic and clinical responses to vaccination with mRNA-electroporated DC in stage III and IV melanoma patients.


METHODS
Twenty-six stage III HLA*02:01 melanoma patients scheduled for radical lymph node dissection (stage III) and 19 melanoma patients with irresectable locoregional or distant metastatic disease (referred to as stage IV) were included. Monocyte-derived DC, electroporated with mRNA encoding gp100 and tyrosinase, were pulsed with keyhole limpet hemocyanin and administered intranodally. TAA-specific T-cell responses were monitored in blood and skin-test infiltrating lymphocyte (SKIL) cultures.


RESULTS
Comparable numbers of vaccine-induced CD8(+) and/or CD4(+) TAA-specific T-cell responses were detected in SKIL cultures; 17/26 stage III patients and 11/19 stage IV patients. Strikingly, in this population, TAA-specific CD8(+) T cells that recognize multiple epitopes and produce elevated levels of IFNγ upon antigenic challenge in vitro, were significantly more often observed in stage III patients; 15/17 versus 3/11 stage IV patients, P = 0.0033. In stage IV patients, one mixed and one partial response were documented. The presence or absence of IFNγ-producing TAA-specific CD8(+) T cells in stage IV patients was associated with marked difference in median overall survival of 24.1 months versus 11.0 months, respectively.


CONCLUSIONS
Vaccination with mRNA-electroporated DC induces a broad repertoire of IFNγ producing TAA-specific CD8(+) and CD4(+) T-cell responses, particularly in stage III melanoma patients.
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
Erik H J G
EH
Aarntzen
Gerty
G
Schreibelt
Kalijn
K
Bol
W Joost
WJ
Lesterhuis
Alexandra J
AJ
Croockewit
Johannes H W
JH
de Wilt
Michelle M
MM
van Rossum
Willeke A M
WA
Blokx
Joannes F M
JF
Jacobs
Tjitske
T
Duiveman-de Boer
Danita H
DH
Schuurhuis
Roel
R
Mus
Kris
K
Thielemans
I Jolanda M
IJ
de Vries
Carl G
CG
Figdor
Cornelis J A
CJ
Punt
Gosse J
GJ
Adema
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D018274:Electroporation; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000008:administration & dosage / Q000235:genetics; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000008:administration & dosage / Q000276:immunology; D058951:gp100 Melanoma Antigen / Q000008:administration & dosage / Q000235:genetics
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D012333:RNA, Messenger; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma; D014442:Monophenol Monooxygenase