The purpose of this study is to determine whether vaccination with melanoma antigen peptides \[Melan-A/Mart-1 (both EAA and ELA), NY-ESO-1b analog, Long NY-ESO-1 LP and MAGE-A10\] and Montanide, CpG adjuvants and low dose rIL-2 can induce an immune response in melanoma patients and to assess the safety of this vaccination.
Current peptide vaccines suffer from low efficiency, since they induce only weak immune activation. We have recently confirmed that in humans the immune response was readily detectable in local lymph nodes while no or only weak activation could be identified in circulating lymphocytes. Increased doses of antigen and adjuvant allow a better extension from local to systemic immune responses. * Group 1 : vaccination with Melan-A analog (ELA) peptide + Montanide * Group 2 : vaccination with Melan-A analog (ELA), NY-ESO-1b analog and MAGE-A10 peptides + Montanide * Group 3: vaccination with Melan-A analog (both EAA and ELA), Mage-A10, NY-ESO-1 peptides+ Montanide + CpG adjuvant * Group 4: vaccination with Melan-A (ELA), Mage-A10,long NY-ESO-1LP peptides + Montanide + CpG * Group 5: vaccination with Melan-A (both EAA and ELA), Mage-A10, long NY-ESO-1 LP peptides + Montanide + CpG + low dose rIL-2
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
39
A maximum of 3 vaccination cycles (cycles 1-3) has been given, each cycle consisting of 4 vaccines in 4 week intervals. The intervals between cycles were 8 weeks. After 3 cycles, patients without major tumor progression requiring other treatment who showed an immunological response received "booster vaccinations" every 3 months.
A maximum of 3 vaccination cycles (cycles 1-3) has been given, each cycle consisting of 4 vaccines in 4 week intervals. The intervals between cycles were 8 weeks. After 3 cycles, patients without major tumor progression requiring other treatment who showed an immunological response received "booster vaccinations" every 3 months.
Oncology Department, Lausanne University Hospital (CHUV) and University of Lausanne
Lausanne, Canton of Vaud, Switzerland
Division of Oncology at the Geneva University Hospital
Geneva, Switzerland
Change From Baseline in Mean Number of Adverse Events (Serious and Non Serious Events)
Safety of the vaccination was assessed according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale. The adverse events (AE) and serious adverse events (SAE) were registered at each study visit during the 3 vaccination cycles and boost cycles.
Time frame: Change from baseline to end of Cycle 1 (3 months), end of Cycle 2 (8 months), end of Cycle 3 (13 months) and end of Boost Cycles (18 months to 23 months).
Fold Change From Baseline in ex Vivo Melan-A-specific CD8+ T Cells Frequency During the Vaccination Period
Ex vivo frequency of Melan-A-specific CD8+ T cells was measured by multimer technique (tetramer assay) in a multicolor flow cytometry analysis. The fold change for each time point compared to baseline was calculated as: Melan-A-specific CD8+ T cell frequency at the time point/ Melan-A-specific CD8+ T cell frequency at baseline. Significant T cell response is defined by at least 2-fold change of Melan-A-specific CD8+ T cell frequency as compared to pre-immunotherapy.
Time frame: Fold change from baseline in Melan-A-specific CD8+T-cells at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months).
Fold Change From Baseline in ex Vivo Frequency of Melan-A-specific IFN-γ-secreting CD8+ T Cells During the Vaccination Period
Ex vivo frequency of Melan-A-specific CD8+ T cells producing IFN-γ (Interferon-gamma) was measured through the Enzyme-Linked Immunosorbent Spot (ELISpot) assay. The fold change for each time point compared to baseline was calculated as: Melan-A-specific IFN-γ-secreting CD8+ T cell frequency at the time point/ Melan-A-specific IFN-γ-secreting CD8+ T cell frequency at baseline.
Time frame: Fold change from baseline in Melan-A-specific IFN-γ-secreting CD8+T-cells frequency at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
Fold Change From Baseline in ex Vivo Frequency of NY-ESO-1-specific CD8+ T Cells During the Vaccination Period
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A maximum of 3 vaccination cycles (cycles 1-3) has been given, each cycle consisting of 4 vaccines in 4 week intervals. The intervals between cycles were 8 weeks. After 3 cycles, patients without major tumor progression requiring other treatment who showed an immunological response received "booster vaccinations" every 3 months.
A maximum of 3 vaccination cycles (cycles 1-3) has been given, each cycle consisting of 4 vaccines in 4 week intervals. The intervals between cycles were 8 weeks. After 3 cycles, patients without major tumor progression requiring other treatment who showed an immunological response received "booster vaccinations" every 3 months.
A maximum of 3 vaccination cycles (cycles 1-3) has been given, each cycle consisting of 4 vaccines in 4 week intervals. The intervals between cycles were 8 weeks. After 3 cycles, patients without major tumor progression requiring other treatment who showed an immunological response received "booster vaccinations" every 3 months.
Ex vivo frequency of NY-ESO-1-specific CD8+ T cells was measured by multimer technique (tetramer assay) in a multicolor flow cytometry analysis. The fold change for each time point compared to baseline was calculated as: NY-ESO-1-specific CD8+ T cell frequency at the time point/ NY-ESO-1-specific CD8+ T cell frequency at baseline.
Time frame: Fold change from baseline in NY-ESO-1-specific CD8+T-cells at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
Fold Change From Baseline in ex Vivo Frequency of NY-ESO-1-specific IFN-γ-secreting CD8+ T Cells During the Vaccination Period
Ex vivo frequency of NY-ESO-1-specific CD8+ T cells producing IFN-γ (Interferon-gamma) was measured through the Enzyme-Linked Immunosorbent Spot (ELISpot) assay. The fold change for each time point compared to baseline was calculated as: NY-ESO-1-specific IFN-γ-secreting CD8+ T cell frequency at the time point/ NY-ESO-1-specific IFN-γ-secreting CD8+ T cell frequency at baseline.
Time frame: Fold change from baseline in NY-ESO-1-specific IFN-γ-secreting CD8+T-cells frequency at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
Fold Change From Baseline in ex Vivo Frequency of MAGE-A10-specific CD8+ T Cells During the Vaccination Period
Ex vivo frequency of MAGE-A10-specific CD8+ T cells was measured by multimer technique (tetramer assay) in a multicolor flow cytometry analysis. The fold change for each time point compared to baseline was calculated as: MAGE-A10-specific CD8+ T cell frequency at the time point/ MAGE-A10-specific CD8+ T cell frequency at baseline.
Time frame: Fold change from baseline in MAGE-A10-specific CD8+T-cells at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
Fold Change From Baseline in ex Vivo Frequency of MAGE-A10-specific IFN-γ-secreting CD8+ T Cells During the Vaccination Period
Ex vivo frequency of MAGE-A10-specific CD8+ T cells producing IFN-γ (Interferon-gamma) was measured through the Enzyme-Linked Immunosorbent Spot (ELISpot) assay. The fold change for each time point compared to baseline was calculated as: MAGE-A10-specific IFN-γ-secreting CD8+ T cell frequency at the time point/ MAGE-A10-specific IFN-γ-secreting CD8+ T cell frequency at baseline.
Time frame: Fold change from baseline in MAGE-A10-specific IFN-γ-secreting CD8+T-cells frequency at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
Percentage of in Vitro Stimulated NY-ESO-1 Lp-specific IFN-γ/TNF-α -Secreting CD4+ T Cells During the Vaccination Period
For each patient, total CD4+ T-cells were stimulated in the presence of peptide NY-ESO-1 long peptide (lp). After 10 days, cell cultures were challenged for 4h with the peptide or left unchallenged. The activation of NY-ESO-1 long peptide (lp)-specific CD4+ T cells were analyzed in vitro by Intracellular Cytokine Staining (ICS) via detection of IFN-γ (Interferon-gamma) and TNF-α (Tumor Necrosis Factor-alpha) producing cells.
Time frame: Percentage of NY-ESO-1 lp-specific IFN-γ/TNF-α -secreting CD4+ T-cells at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
Percentage of in Vitro Stimulated NY-ESO-1 Lp-specific IFN-γ/TNFα -Secreting CD8+ T Cells During the Vaccination Period
For each patient, total CD8+ T cells were stimulated in the presence of peptide NY-ESO-1 long peptide (lp). After 10 days, cell cultures were challenged for 4h with the peptide or left unchallenged. The activation of NY-ESO-1 long peptide (lp)-specific CD8+ T cells were analyzed in vitro by Intracellular Cytokine Staining (ICS) via detection of IFN-γ (Interferon-gamma) and TNF-α (Tumor Necrosis Factor-alpha) producing cells.
Time frame: Percentage of NY-ESO-1 lp-specific IFN-γ/TNF-α -secreting CD8+ T cells at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
Disease Status Assessment During the Vaccination Period
The disease status was assessed by computed tomography (CT) or positron emission tomography (PET)/CT at baseline and after the fourth vaccination of each cycle. During the "booster vaccines" period, imagery examinations were performed every 3 months for patients with measurable disease and every 6 months for patients with non measurable disease. The tumor response was assessed according to the classification World Health Organization (WHO) 1979 and defined as: * No Evidence of Disease (NED) * Stable disease (SD): Change in size of all measurable lesions (the sum of the products of the greatest and perpendicular parameters), of less than a 25% increase or 25% decrease from baseline for at least 4 weeks, without appearance of new lesions or progression of any lesion. * Progressing disease (PD): Appearance of new tumors, or increase in size of any measurable tumor by at least 25% of the sum of the product of the greatest and perpendicular diameter.
Time frame: Disease status at baseline, after cycle 1 (3 months), after cycle 2 (8 months), after cycle 3 (13 months) and if applicable after boost cycles (16 months, 19 months or 22 months)