Immunologic and clinical effects of injecting mature peptide-loaded dendritic cells by intralymphatic and intranodal routes in metastatic melanoma patients.
OBJECTIVE
A phase I/II trial was conducted to evaluate clinical and immunologic responses after intralymphatic and intranodal injections of mature dendritic cells.


METHODS
Fourteen patients with a metastatic melanoma received matured dendritic cells, loaded with Melan-A/MART-1 and/or NA17-A peptides and keyhole limpet hemocyanin. The cells were matured overnight with Ribomunyl, a toll-like receptor ligand, and IFN-gamma, which ensured the production of high levels of interleukin-12p70. Dendritic cells were injected at monthly intervals, first into an afferent lymphatic and then twice intranodally. Immunologic responses were monitored by tetramer staining of circulating CD8(+) lymphocytes and delayed-type hypersensitivity tests.


RESULTS
Dendritic cell vaccination induced delayed-type hypersensitivity reactivity toward NA17-A-pulsed, keyhole limpet hemocyanin-pulsed, and Melan-A-pulsed dendritic cells in 6 of 10, 4 of 11, and 3 of 9 patients, respectively. Four of the 12 patients analyzed by tetramer staining showed a significantly increased frequency of Melan-A-specific T cells, including one patient vaccinated only with NA17-A-pulsed dendritic cells. Furthermore, 2 of the 12 analyzed patients had a significant increase of NA17-A-specific T cells, including one immunized after an optional additional treatment course. No objective clinical response was observed. Two patients were stabilized at 4 and 10 months and three patients are still alive at 30, 39, and 48 months.


CONCLUSIONS
Injections into the lymphatic system of mature peptide-loaded dendritic cells with potential TH1 polarization capacities did not result in marked clinical results, despite immunologic responses in some patients. This highlights the need to improve our understanding of dendritic cell physiology.
Lesimple
Thierry
T
Centre Eugène Marquis, Rennes, France.
Neidhard
Eve-Marie
EM
Vignard
Virginie
V
Lefeuvre
Claudia
C
Adamski
Henri
H
Labarrière
Nathalie
N
Carsin
André
A
Monnier
Delphine
D
Collet
Brigitte
B
Clapisson
Gilles
G
Birebent
Brigitte
B
Philip
Irène
I
Toujas
Louis
L
Chokri
Mohamed
M
Quillien
Véronique
V
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000917:Antibody Formation; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use; D003713:Dendritic Cells / Q000737:chemistry / Q000637:transplantation*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D007272:Injections, Intralymphatic / Q000379:methods; D008207:Lymphatic Metastasis / Q000276:immunology / Q000473:pathology; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D016019:Survival Analysis; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010455:Peptides