Adenovirus MART-1-engineered autologous dendritic cell vaccine for metastatic melanoma.
We performed a phase 1/2 trial testing the safety, toxicity, and immune response of a vaccine consisting of autologous dendritic cells (DCs) transduced with a replication-defective adenovirus (AdV) encoding the full-length melanoma antigen MART-1/Melan-A (MART-1). This vaccine was designed to activate MART-1-specific CD+8 and CD4+ T cells. Metastatic melanoma patients received 3 injections of 10(6) or 10(7) DCs, delivered intradermally. Cell surface phenotype and cytokine production of the DCs used for the vaccines were tested, and indicated intermediate maturity. CD8+ T-cell responses to MART-1 27-35 were assessed by both major histocompatibility complex class I tetramer and interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISPOT) before, during, and after each vaccine and CD4+ T-cell responses to MART-1 51-73 were followed by IFN-gamma ELISPOT. We also measured antigen response breadth. Determinant spreading from the immunizing antigen MART-1 to other melanoma antigens [gp100, tyrosinase, human melanoma antigen-A3 (MAGE-A3)] was assessed by IFN-gamma ELISPOT. Twenty-three patients were enrolled and 14 patients received all 3 scheduled DC vaccines. Significant CD8+ and/or CD4+ MART-1-specific T-cell responses were observed in 6/11 and 2/4 patients evaluated, respectively, indicating that the E1-deleted adenovirus encoding the cDNA for MART-1/Melan-A (AdVMART1)/DC vaccine activated both helper and killer T cells in vivo. Responses in CD8+ and CD4+ T cells to additional antigens were noted in 2 patients. The AdVMART1-transduced DC vaccine was safe and immunogenic in patients with metastatic melanoma.
Butterfield
Lisa H
LH
Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. butterfieldl@upmc.edu
Comin-Anduix
Begonya
B
Vujanovic
Lazar
L
Lee
Yohan
Y
Dissette
Vivian B
VB
Yang
Jin-Quan
JQ
Vu
Hong T
HT
Seja
Elizabeth
E
Oseguera
Denise K
DK
Potter
Douglas M
DM
Glaspy
John A
JA
Economou
James S
JS
Ribas
Antoni
A
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D016233:Immunotherapy, Active / Q000009:adverse effects; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology*; D009367:Neoplasm Staging; D015202:Protein Engineering; D014161:Transduction, Genetic; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016056:Immunodominant Epitopes; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins