Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T-Cell Responses in Metastatic Melanoma Patients--Report of a Phase I/IIa Clinical Trial.
OBJECTIVE
Cancer vaccines aim to generate and maintain antitumor immune responses. We designed a phase I/IIa clinical trial to test a vaccine formulation composed of Montanide ISA-51 (Incomplete Freund's Adjuvant), LAG-3Ig (IMP321, a non-Toll like Receptor agonist with adjuvant properties), and five synthetic peptides derived from tumor-associated antigens (four short 9/10-mers targeting CD8 T-cells, and one longer 15-mer targeting CD4 T-cells). Primary endpoints were safety and T-cell responses.


METHODS
Sixteen metastatic melanoma patients received serial vaccinations. Up to nine injections were subcutaneously administered in three cycles, each with three vaccinations every 3 weeks, with 6 to 14 weeks interval between cycles. Blood samples were collected at baseline, 1-week after the third, sixth and ninth vaccination, and 6 months after the last vaccination. Circulating T-cells were monitored by tetramer staining directly ex vivo, and by combinatorial tetramer and cytokine staining on in vitro stimulated cells.


RESULTS
Side effects were mild to moderate, comparable to vaccines with Montanide alone. Specific CD8 T-cell responses to at least one peptide formulated in the vaccine preparation were found in 13 of 16 patients. However, two of the four short peptides of the vaccine formulation did not elicit CD8 T-cell responses. Specific CD4 T-cell responses were found in all 16 patients.


CONCLUSIONS
We conclude that vaccination with IMP321 is a promising and safe strategy for inducing sustained immune responses, encouraging further development for cancer vaccines as components of combination therapies.
Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland.
Amandine
A
Legat
Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland.
Hélène
H
Maby-El Hajjami
Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland.
Petra
P
Baumgaertner
Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland. Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland.
Laurène
L
Cagnon
Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland. Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland.
Samia
S
Abed Maillard
Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland.
Christine
C
Geldhof
Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland.
Emanuela M
EM
Iancu
Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland.
Luc
L
Lebon
TCMetrix, Epalinges, Switzerland.
Philippe
P
Guillaume
TCMetrix, Epalinges, Switzerland.
Danijel
D
Dojcinovic
Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland.
Olivier
O
Michielin
Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland.
Emanuela
E
Romano
Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland.
Grégoire
G
Berthod
Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland.
Donata
D
Rimoldi
Immutep, SA, Orsay, France.
Frédéric
F
Triebel
TCMetrix, Epalinges, Switzerland.
Immanuel
I
Luescher
Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland. Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland.
Nathalie
N
Rufer
Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland. Department of Oncology, Lausanne University Hospital Center (CHUV) and University of Lausanne, Lausanne, Switzerland. doc@dspeiser.ch.
Daniel E
DE
Speiser
D015703:Antigens, CD / Q000737:chemistry / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D018655:Lymphocyte Count; D058965:MART-1 Antigen / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D010455:Peptides / Q000276:immunology*; D016896:Treatment Outcome; D014611:Vaccination; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D015415:Biomarkers; D019496:Cancer Vaccines; D058965:MART-1 Antigen; D010455:Peptides; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human; C000720328:soluble LAG-3 protein, human