Design of this trial: sequential adaptive design, 2nd cohort, mature DC transfected with RNA encoding MelanA, Mage3 and Survivin +/- E/L-selectin, i.v. route, 13 evaluated patients. Comparison of pre-existing and vaccine-induced immune responses in stage IV melanoma patients. We have efficiently transfected DC with RNA encoding a functional protein (E/L-selectin), which allows entry of DC into LN from HEV. These DC rolled in vitro on sialyl-LewisX-coated slides, and in vivo, mouse E/L-selectin-transfected DC homed to LN after i.v. application. Monocyte-derived and...

We obtained data on anti-tumor responses in melanoma patients that were vaccinated with autologous DCs loaded with a combination of tumor Ag peptides. This study is a collaboration with the lab of Didier Colau and Thierry Boon in Brussels. HLA-DP4/MAGE3 molecules have been prepared to stain ex vivo PBL from immunized melanoma patients.

High-throughput data is available on tumour-associated antigen (TAA) specific T-cells in breast cancer patients using the Becton Dickinson Lyoplate™ technology. Therefore we have established multiparameter assessments of antigen-specific CD4+ and CD8+ T-cells enabling a simultaneous quantitative and qualitative analysis.

First clinical vaccination data has been obtained using an HSV vector expressing full length tyrosinase, gp100 and MART-1 to transduce DC from melanoma patients. Biovex has developed HSV-based vectors optimised for antigen delivery to dendritic cells by the deletion of HSV genes which usually inhibit DC function. These deliver antigens to DC at very high efficiency and activate the transduced cells similarly to LPS. Based on this technology, Biovex began a clinical program where an HSV vector expressing full length tyrosinase, gp100 and MART-1 was used to transdu...

We are collecting immunological data from a melanoma patient, aiming to identify the antigen(s) recognized by T cells from this patient that experienced an outstanding response to immunotherapy. This patient received several adoptive T cell transfers and regressed from stage IV melanoma to a disease free state and has remained tumor free for several years. In a collaboration with Dr. O. Winqvist, Karolinska Institute, we attempted to improve the adoptive transfer protocol by stimulating T cells with monocyte derived DC pulsed with tumor lysate, instead of simply a...

Using the MLPC/tetramer method described last year, we obtained data by pursuing the immunological monitoring of melanoma patients vaccinated with 4 peptides (MAGE-A3, gp100, NA17 and tyrosinase) presented by HLA-A2. We measured responses to these peptides injected with Montanide, but did not know whether the Montanide adjuvant was important for these T cell responses. Indeed, melanoma patients may mount spontaneous responses to these antigenic peptides. We therefore injected the same peptides without adjuvant, and no response was observed. We conclude that Montan...

Our lab conducted an immunomonitoring study, such as on effector memory T cells, which led to corresponding immunological data.

We have obtained data from monitoring vaccine induced T cell responses for two clinical trials. We found CD8+ and CD4+ T cell responses against the immunological tracers KLH and TK, and against the NTPs and MAGE-3, respectively. Assays used have been 3H-thymidine-incorporation, ELISA, CBA, LDA and 51Cr-release assays. Autologous tumour specific CD8+ and CD4+ T cell clones have also been obtained from the blood and tumour infiltrating lymphocytes. We investigated the role of spontaneous CD4+ T cell responses against the HPV-18 and 16 E6 and E7 proteins in women wi...

The initiation of a multi partner trial is planned and data will be generated. The DC-THERA trial will compare the use of ‘TRI-MIX’ RNA in clinical trials that were already underway at each of the three centres (Nijmegen Medical School, Nijmegen; Friedrich-Alexander University, Erlangen; Vrije Universiteit Brussel, Brussels). It was decided that Friedrich-Alexander University, Erlangen, would apply for a licence to prepare GMP-grade ‘TRI-MIX’ RNA and subsequently supply this for all three centres. The multi-centre trial is a well-standardised, two-arm, m...

Data has been obtained from our phase 1 HIV clinical study described here: Study Design: Patients that are successfully treated with highly active anti-retroviral therapy (HAART) with no measurable viral load AND have a cryopreserved infectious plasma sample that was drawn immediately prior to initiation of HAART are administered 4 monthly doses of the Arcelis product. Current status: This trial is fully enrolled. Immune response data is encouraging in the first 7 patients for which the analysis has been completed. Six of 7 patients developed CD8+ T-cell immune...

Data was obtained on the efficacy in a phase I/II study investigating multiple injections of CLL-DCV01 in patients with previously treated B-cell chronic lymphocytic leukemia. This study is fully enrolled (n=9). Efficacy data will be assessed via tumor burden data collected over the next two months. Absolute lymphocyte counts and immunomonitoring data will be compiled by the end of Q1’08.

The study protocol that will be used for this trial has been reviewed by the local ethical committee and is now ready to be submitted to Läkemedelsverket, the Swedish regulatory authority for clinical trials. Upon approval by Swedish authorities we plan to include, treat and evaluate 10 patients during a period of one to two years. It will probably start in 2009 and data will become available.

We have obtained data from a phase I long peptide vaccination trial with p53 peptides in Montanide adjuvant in patients with colorectal cancer or ovarium cancer. This vaccine was well tolerated and robust p53-specific T cell responses were induced. In the future we intend to combine the p53 vaccine with other cancer therapies such as chemotherapy.

In our lab, data was obtained from a phase I trial using peptide-pulsed Dex. Dendritic cell (DC) derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes promoting T cell -dependent tumor rejection. In this Phase I trial using peptide-pulsed Dex, the observation of clinical regressions in the absence of T cell responses prompted the search for alternate effector mechanisms. Mouse studies unraveled the bioactivity of Dex onto NK cells, Dex promoting a IL-15Ra-dependent NK cell proliferation and a NKG2D-dependent activation resulting...

We have obtained data from a phase I/II clinical trial of patients with end stage cervical cancer and of patients with vulvar intraepithelial neoplasia (VIN) grade III. Preclinical animal studies have shown that long peptides of 25-35 amino acids in length upon injection are only processed efficiently for MHC class I by dendritic cells in vivo. Long peptide injection is followed by appropriate cognate interactions between such DC, CD4+ T helper cells and CD8+ CTL precursors. Three groups of end stage cervical cancer patients (in total N=35) were subcutaneously va...

Data will become available on the safety, antitumoral immune response and DC migration in the organism in patients with advance renal cell carcinoma and melanoma from this trial using cellular immunotherapy with dendritic cells loaded with tumor antigens. This study is not yet open for participant recruitment. ClinicalTrials.gov Identifier: NCT00610389 Purpose Background: cellular immunotherapy with dendritic cells (DC) loaded with tumor antigens has shown clinical activity, although in a small number of patients. Therefore, it is mandatory to improve the resul...

A worldwide first randomized adjuvant trial in a subgroup of high risk melanoma patients (monosomy 3) using autologous DC transfected with amplified total tumor RNA derived from patients' uvea melanomas was to be started in 2009 and data will become available.

Data have been obtained from a phase 2 study testing PME-CD40L DC in RCC patients with clear cell histology. The Phase 2 trial has the same general design, dosing regimen, endpoints, and immunomonitoring plan as the completed RCC trial. However, the Phase 2 study tests the improved RCC product (i.e., PME-CD40L DC) and is restricted to RCC patients with clear cell histology. As predicted from the in vitro data, the improved PME-CD40L DC product does indeed lead to restoration of both IL-2 and IFN-? responses. Also consistent with our in vitro observation is the...

Data has been obtained on the BRAF/NRAS mutation status and expression of COX-2 and iNOS comparing their prognostic value for overall survival in stage III malignant melanoma. New prognostic markers for malignant melanoma are urgently needed. Inducible nitric oxide synthase (iNOS) and cyclooxygenase type 2 (COX-2) have been described to correlate with progression of melanoma. Moreover, activating mutations in BRAF/NRAS oncogenes are often detected in melanoma. We have examined the BRAF/NRAS mutation status and expression of COX-2 and iNOS to compare their progno...