Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma.
OBJECTIVE
Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma.


METHODS
Autologous DC were pulsed with MART-1(26-35) peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point.


RESULTS
Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response.


CONCLUSIONS
The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.
Department of Medicine, Division of Hematology/Oncology, University of California at Los Angeles, Los Angeles, California 90095-1782, USA. aribas@mednet.ucla.edu
Antoni
A
Ribas
Begoña
B
Comin-Anduix
Bartosz
B
Chmielowski
Jason
J
Jalil
Pilar
P
de la Rocha
Tara A
TA
McCannel
Maria Teresa
MT
Ochoa
Elizabeth
E
Seja
Arturo
A
Villanueva
Denise K
DK
Oseguera
Bradley R
BR
Straatsma
Alistair J
AJ
Cochran
John A
JA
Glaspy
Liu
L
Hui
Francesco M
FM
Marincola
Ena
E
Wang
James S
JS
Economou
Jesus
J
Gomez-Navarro
D000328:Adult; D000368:Aged; D019138:Antibodies, Blocking / Q000008:administration & dosage* / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D020014:K562 Cells; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; C520704:tremelimumab