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A Phase IB/II Study of Immunotherapy with Autologous Dendritic Cells Pulsed with Multiple HLA-A2 and MAGE-3.DP4 Peptides in Metastatic Cutaneous Melanoma Patients

clinical study dataset

At the end of 2004 BruCells has initiated two identical clinical studies entitled: “A Phase IB/II Study of Immunotherapy with Autologous Dendritic Cells Pulsed with Multiple HLA-A2 and MAGE-3.DP4 Peptides in Metastatic Cutaneous Melanoma Patients”. Patients received sequential immunizations with autologous dendritic cells pulsed with 8 HLA-restricted HLA-A2 peptides and a MAGE-3.DP4 peptide. They were randomized to receive immunizations either with I3 DC (DC generated with interferon-beta and interleukin-3) or with G4 DC (DC generated with GM-CSF and IL-4). At the end of 2005 the study was prematurely terminated due to low recruitment, data on patient responses is available.

2 patients received vaccines up to cycle 3. One of them is an I3 patient (E501) who has received 9 vaccines with peptides only. The other one is a G4 patient (E507) who has received 6 vaccines with peptide only. Both patients received a sequence of six immunizations every two weeks, consisting of autologous dendritic cells loaded with the 8 HLA-A2 restricted peptides and MAGE.3-DP4 in Cycle 1. In Cycle 2, they received a sequence of three immunizations every six weeks, consisting of autologous dendritic cells loaded with the 8 HLA-A2 restricted peptides and MAGE.3-DP4. Initially, in Cycle 3, immunizations have been continued with peptide-only injections of all 9 peptides except Tyrosinase at 12 weeks intervals. For the continuation of the vaccinations the clinicians have decided to inject the patients at 6 months intervals. Both patients who clinically showed Partial Response at the end of cycle 1 are currently doing well under this treatment, but at the beginning of 2008 the vaccination program has been ended.
Both patients had clinically shown Partial Response at the end of cycle 1 and were in complete remission in the course of cycle 3.

For the analysis of the immune responses, specific CTL directed against the 8 antigens was assessed by using restimulation in vitro, followed by staining with the corresponding tetramer and cloning of the tetramer-positive lymphocytes. The result of these tests were considered positive if the post-immunization frequency of the different anti-TAA CTLp among the CD8+ T cells was 10-fold higher than the one encountered before vaccination.
For both patients the tests were performed on frozen peripheral blood leukocytes (PBL) obtained from leukapheresis or buffy-coat collections performed before and after the 6 vaccinations in Cycle 1 and after the 3 vaccinations of Cycle 2.

The fresh PBL samples were collected from UTCM (Hôpital Erasme, ULB) and were transferred to Ludwig Institute where the freezing of the samples and analyses were performed.

Frequencies of precursors of CD8 T cells stained by a tetramer containing the specific peptide had shown for patient E501 post-vaccination frequencies of the T cells of anti-NY-ESO-1.A2 and anti-Tyrosinase.A2 that were >=10-fold higher than that of pre-vaccinations, indicating a specific CTL response to these vaccinations.

An analysis performed on PBL collected after the 3 vaccinations of cycle 2 clearly shows that the frequencies for both anti-NY-ESO-1.A2 and anti-Tyrosinase.A2 T cells are still elevated.

For E507 no immunological response to the vaccinations had been observed after cycle 1 and a new analysis on PBL collected after cycle 2 did not show any change.




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