Our lead product for the treatment of cancer is OncoVex GMCSF. OncoVexGMCSF is completing a 50-patient Phase II clinical trial for the treatment of unresectable metastatic melanoma, as a monotherapy, in the second line/salvage therapy setting. Data so far indicates that OncoVex can destroy both injected and un-injected melanoma deposits. The trial is still in progress.

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 ...

We found that Indium111 labelled DC should not be loaded with tumor antigens if applied in patients, which may result in loss of specific immune responses and are testing this in-vivo. Analysis of DC migration in vivo in a first patient by i.v. application of indium labelled E/L-S DC (without antigen loading) is scheduled for March 2009. Data will become available.

Data has been obtained in a study of antigen recognition of blood-derived T cells. In this study, an IFNgamma ELISPOT was done with PBMC loaded with peptide pools, each consisting of 10 15-mers, which overlap with 11 aminoacids.

Data have been obtained on the antigen recognition of DTH infiltrating T cells. To obtain the data, activation of CD4 and CD8 T cells upon recognition of EBV-B cells expressing vaccinal antigens was evaluated by CD137 upregulation, CD107a and CD40L expression using flow cytometry. Luminex technology was used to quantify the TNFalpha and IFNgamma secretion.

We have obtained data from an analysis of antigen loading of DCs via targeting DC-SIGN, which resulted in enhanced class II-mediated presentation. Constructs for fusion proteins of the DC specific receptor DC-SIGN fused to GFP have been generated.

(This trial is expected for 2009 and data will become available.)

In 2008 we have started a trial in patients with VIN3 disease (similar to the Phase I/II clinical trial on the use of long peptides plus adjuvant for end-stage cervical cancer or VIN patients), in which we are comparing the efficacy of this vaccine with or without local application at the vaccination site of the TLR ligand imiquimod (Aldara). Results and data will become available.

Our lab obtained first data from a new clinical trial of a DC vaccine administered into irradiated tumours in RCC. Three patients were enrolled and DC vaccine was produced. However only one patient received the vaccine due to cancer progression in the other two patients. The DC were labelled with 111In. The following patients will receive DC labelled with Endorem and the vaccine will be imaged with MRI. The patient treated is in complete remission 6 months after treatment.

We obtained data from a trial in small cohorts of patients (3-9) who were vaccinated with differently composed DC-vaccines: DC loaded with a single MAA-derived peptide (MAGE-3.A1 or -A2 or Na17.A2) or pulsed with 2 to 3 MAA-derived peptides (combinations of MAGE-3.A2, MAGE-C2.A2 or Na17.A2) or G4-DC loaded with 8 different peptides. Our experiences can be summarized as follows: (1) preparation of an autologous dendritic cell based vaccine was feasible for every patient enrolled in our studies; (2) we did not observe vaccination related toxicities beside mild...

We have continued recruitment of patients and obtained first data in the two clinical trials of active vaccination in metastatic melanoma. Structural works that have been performed to up-grade the GMP facility for conduction of phase III clinical trials has limited the number of patients recruited. Nonetheless, we were able to complete the vaccination schedule in 4 patients and to perform additional injections in disease free patients, in patients with stable disease or with slowly progressive disease. We could not recruit new patients because the generation in GM...

We have further data available on a clinical trial on vaccination of B-CLL patients with autologous, apoptotic, leukemic cells (Apo-DC). Cohort 1 with the vaccine alone and cohort 2 (5 patients) combining the vaccine together with GM-CSF as an adjuvant has finished accrual and all patients in these two cohorts have been monitored for 52 weeks. The clinical and immune monitoring data is being currently analyzed. The third cohort consisting of the vaccine and GM-CSF administered after a single dose of cyclophosphamide (300 mg/ sq. meter) is currently being accrued...

Our lab obtained data on the ability of NK cell IFN-gamma production to predict long term survival in advanced GISTs treated with IM. Background: Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for imatinib mesylate (IM) (Gleevec®, Novartis), a specific inhibitor of these tyrosine kinase receptors. Predictive factors for the response to IM pertain to the intrinsic features of GIST tumor cells but not to the host. Besides its direct antiproliferative activity on tumor cells, I...

A phase I/II study of immunization of HIV infected individuals stable under HAART has been initiated which will provide us with immunological data. These patients are being vaccinated with cytokine cocktail matured DCs electroporated with mRNA encoding Tat, Rev and Nef. The cDNA’s encoding these early expressed HIV antigens have been human codon optimized and modified with lysosomal targeting sequences. Four vaccines separated by 4 weeks. Two weeks after the 4th vaccine, an analytical HAART interruption was started. So far, 17 patients have been included in t...

During the previous period we obtained data from our continued pilot clinical trials of DC-based immunotherapy of melanoma patients. After an initial cohort of patients treated with monocyte-derived DCs matured with inflammatory cytokines and subsequently electroporated with mRNA encoding 6 tumor-associated antigens, we persued this trial in a next cohort where DC-based vaccines were combined with low dose IFN-alfa (3 x 10e6 U per wk). In a significantly higher number of patients we observed vaccine-induced depigmentation and vitiligo. Further improvement and ca...

Summary of the completed RCC clinical study and the data obtained: RCC subjects were deficient in T cell IFN-gamma and IL-2 production pre-vaccination. The IL-2 defect was corrected in 7/12 patients post-vaccination. Vaccination resulted in an increase in tumor antigen-specific T cells in 8/12 patients. 7/12 subjects had a response to more than one antigen post-vaccination. Median overall survival was ~25 months compared to ~11 months for historical controls (confirmed by matched pair analysis).

We are planning clinical trials of melanoma patients treated with DC and tumour lysate plus adoptive transfer of T cells which will result in corresponding data.

Our laboratory has data on autologous dendritic cells loaded with apoptotic leukemic cells from patients with B-CLL used as vaccine in patients. In preclinical experiments DC-loaded with apoptotic leukemic cells were shown to induce a strong preferentially Th1 T-cell response. Apoptotic tumor cells were more effective than lysate, RNA and cell hybrids. A clinical trial has been initiated where autologous dendritic cells are loaded with apoptotic leukemic cells from patients with B-CLL. So far “vaccines” have been produced for six patients. Four patients are...

Our lab has data from an interim statistical analysis of the DERMA-ER-DC 04 trial (multipeptide loaded cytokine matured moDC +/- CD40L activation, 70 evaluated patients). This analysis for the first time showed a clinical correlation of induced immune responses as measured in the blood with outcome, as there have been so far statistically significantly less events in stage III patients showing good CTL reponses (IFN-y Elispot) to multiple class I and II peptides compared to low responders of the stage III cohort. Additional in vitro maturation of DC by CD40L (leuci...

We have data from a clinical trial with melanoma patients (stage IV, documented progress) receive DC transfected with RNA encoding MelanA, Mage3 and Survivin +/- E/L-selectin by the i.v. route. This DERMA-ER-DC 05 trial (multipeptide loaded cytokine matured moDC + prior Treg elimination by 3x ONTAK treatment [5µg/kg], 8 evaluated pat.) did not show any enhanced immune reponses compared to the equivalent cohort in the DERMA-ER-DC 04 trial. Patient recruitment into the 2nd phase of the DERMA-ER-DC 06 trial has started (sequential adaptive design). Immunomonitori...