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Development of cancer immunotherapy and stem cell therapy based on an artificial thymus technology platform

We aim to develop antigen specific t cells against different muc1 glycoforms by means of differentiating stem cells in an artificial thymus towards dcs and t cells. These dcs will be transduced with ad-muc1 and given to t cells to generate antigen specific t cells that can be cloned.

Since current treatment options (surgery, chemotherapy and radiotherapy) unfortunately fail in over 50% of cancer patients, new treatment options are needed. One of these options is immunotherapy. This can be realised by several methods. One of them is making use of a donor immune system, such as in allogeneic transplantation. Another option is to stimulate the body's own immune system (active vaccination). Other possible options are antibody treatments and the adoptive transfer of immuno-competent cells. The principal idea of an immune vaccine in general is to stimulate the patient's immune system against certain threats like infectious agents or cancer. In cancer, however, it is difficult for the immune system to develop an anti-cancer response. The cancer cell by itself does not spontaneously activate the immune system in most of the cases. However in the scientific world, evidence is accumulating and showing that cancer vaccines can be realised. In clinical trials worldwide it has been demonstrated that a certain percentage of patients (10-20%) responds to a cancer vaccine with partial or complete disappearance of the disease. However further improvements have to be made. Among the various techniques used to improve cancer vaccines, the dendritic cell (DC) plays a crucial role. The DC is essential in the activation of the whole immune system in-vivo. By loading DC with tumour parts (peptides, proteins), it is possible to activate the immune system against the whole tumour. Through this activation, a subset of white blood cells called T cells are mobilised to kill the tumour cells. The AZM is developing a cancer vaccine using the Mucine-1 protein for use in patients with breast cancer. Mucine-1 is usually present on healthy epithelial cells. However it is also present in over 80% of tumours like breast cancer, lung cancer, ovarian cancer, multiple myeloma and acute myeloid leukaemia. In cancer cells the protein Mucine-1 is differently glycosylated and therefore has a different glycopeptide structure. These glycopeptides will demonstrate new antigenic epitopes to the immune system and therefore can serve as a target for attack by antigen specific T cells in-vivo recognising these new epitopes when properly activated by DCs. The perspectives of a cancer vaccine in breast cancer are enormous. It can be used at various - different - stages of the disease, first of all, to prevent breast cancer in women with a high risk of developing this disease because of a specific chromosomal constitution in the family. In addition, women undergoing treatment still have a high risk (30 - 70%) of developing meta-static diseases. Vaccines might be highly valuable at this point in time for prevention of meta-static diseases. Finally, a vaccine might be used to treat patients that already have meta-static disease to induce tumour responses and possibly prolong life and/or improve quality of life. In other words the perspectives of using a vaccine in breast cancer is enormous with possible high value for health care. So far DC vaccines have been administered to patients with the aim of activating T cells in the patient. A possibility why the DC vaccines have met only limited success so far is an improper T cell activation in-vivo. CYGENICS has developed an in-vitro system called the Cytometrix(R) in which de novo T cell development from adult blood stem cells occurs, including the proper selection of T cells. Including in-vitro generated antigen specific T cells with the DC vaccines should lead to a strong and very specific anti-tumour immune response. In this proposal we will compare the T cells generated de novo from stem cells versus peripheral blood derived T cells as the repertoire of T cells might be different due to negative selection or tolerisation in-vivo. The other approach the AZM is pursuing is an allogeneic stem cell transplantation. In this system, donor immune cells are the most active component of an anti-tumour response. Traditionally the cells most relevant are the T lymphocytes. However there is recent evidence that especially NK cells might be very relevant as well. In our research group we focus on a haploidentical (semi-HLA-identical (Histocompatibility antigen) family donor available in nearly all patients) transplantation. In mouse models, we recently observed that this treatment can cure breast cancer in about 50% of cases (manuscript submitted). In humans it is known that this might be a very good treatment for acute leukaemia. We are presently exploring the role of NK cells in various tumour types. The hypothesis is that adoptive transfer of NK cells might have an anti-tumour response in a variety of cancers. One of the disadvantages of haploidentical transplantation is the severe immune-deficiency in these patients for a certain period of time after the treatment. Patients become susceptible to and often die from opportunistic Cytomegalo Virus (CMV) infection. The treatment of CMV-virus specific T cells might be part of the solution. The current technologies of the partners needed in this research proposal include the generation of dendritic cells, NK cells and antigen specific T cells (AZM), the Cytometrix(R), a thymus-like environment supporting generation of T cells (CYGENICS), in-vitro systems and animal models to study T cell development (RIKEN-RCAI) and a GMP (Good Manufacturing Process) facility and manufacturing technology for generating clinical grade DCs, T cells and NK cells (PHARMACELL). By combining these technologies, we have a central research question for both lines of research: Can antigen specific T cells suitable for clinical applications in cancer be obtained in the Cytometrix(R) system? Specific aims in this project will be: 1. Optimisation of DC cultivation in the Cytometrix(R). 2. Induction tumour-specific T cells in the Cytometrix(R). 3. Scaling up of cell cultures under GMP conditions. 4. Understanding the molecular mechanism. 5. Realisation of NK cell induction and expansion in the Cytometrix. 6. Induction of CMV-specific T cells in the Cytometrix. 7. Automation of process of quality assessment by microscopic imaging. The work packages for aims 1+2+5+6 will be carried out by the AZM. The work package for aim 3 as well as the administration for this project will be carried out by PHARMACELL. The work package for aim 4 will be carried out by the RIKEN INSTITUTE. CYGENICS will make the Cytometrix(R) system available to the partners and will teach the other partners about its use. MAIA-SCIENTIFIC will execute the work package for aim 7.
Acronym: 
PACRIMA
Project ID: 
3 746
Start date: 
01-04-2006
Project Duration: 
36months
Project costs: 
3 440 000.00€
Technological Area: 
Cytology, Cancerology, Oncology
Market Area: 
Pharmaceuticals/fine chemicals

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