Objective
The haematological malignancies comprise the acute and chronic leukaemias, Hodgkin's disease and non-Hodgkin's lymphomas, and multiple myeloma. Many patients are curable with combination chemotherapy, but for those whose disease proves resistant to conventional approaches, the options are few and the outcome is poor. Novel treatment strategies such as gene therapy may improve disease free survival in the long-term but have yet to be proved both safe and effective. In the meantime, autologous stem cell transplantation [ASCT] has been widely used in an attempt to improve outcome. This approach permits the administration of high doses of therapy, as the patient can be rescued from the inevitable bone marrow failure by the reinfusion of cryopreserved autologous stem cells. However the use of ASCT has yet to be optimised. First, stem cells can be derived from the blood or bone marrow but there are qualitative differences between the two sources and the cells may therefore differ in their kinetics of recovery and their durability. Second, despite high dose therapy and stem cell rescue, many patients experience disease recurrence. The relapse may originate from contaminating tumour cells within the cryopreserved stem cells, or from tumour cells within the patients which survived the high dose therapy, or from both sources. This issue is of more than theoretical importance. If tumour cells persist in the transplant products then strenuous efforts should be made to remove them prior to infusion. If the relapse originates from residual tumour cells within the patient, then the emphasis must be on improved methods of tumour eradication. Studies in which unique genetic sequences are introduced into the tumour cells, so as to facilitate their detection later, are currently the only means of resolving this question. If transplantation of genetically manipulated material in this way can be shown to be safe, then the ultimate goal will be to introduce genes whose protein products have a therapeutic role. For this to be successful the transgene must be expressed at a level sufficient to confer a therapeutic benefit, for a sustained period of time. To date clinical progress with therapeutic gene transfer strategies has been disappointing. Furthermore, it has been virtually impossible to perform such studies in Europe. Regulations correctly require that all vectors used for in vivo gene delivery be produced to standards of good manufacturing practice (GMP) and that patients are monitored for prolonged periods of time to exclude potential adverse effects. Although commercial companies are now beginning to offer viral vector production facilities, this is usually at costs prohibitive to academic clinical institutions. Without the availability of vector production at reasonable cost, the progress of gene therapy in Europe has fallen far behind that in the U.S.A. The aim of this proposal is to demonstrate the safety and feasibility of retroviral mediated gene transfer [RMGT] in the management of patients with haematological malignancies. Five teams with extensive expertise in autologous stem cell transplantation [ASCT] will utilise the resources of a recently established academic retroviral vector production facility. Retroviral vectors carrying 'marker genes' will be constructed and validated in vitro in each centre before being produced to standards of good manufacturing practice [GMP] at the production facility. Clinical grade vector will then be used in studies designed to demonstrate; (i) the safety of RMGT in clinical practice, (ii) the origin of relapse after ASCT, (iii) the kinetics of reconstitution of stem cells derived from blood and bone marrow, (iv) the durability of engraftment and the duration of expression of the transgene, and thereby evaluate the ability of transduced stem cells to sustain the delivery of therapeutically useful products, (v) the role of drug resistance genes in the management of haematological malignancies,and (vi) to determine the ability of transduced genes to elicit an immune mediated response.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences medical biotechnology genetic engineering gene therapy
- medical and health sciences basic medicine pharmacology and pharmacy drug resistance
- medical and health sciences medical biotechnology cells technologies stem cells
- medical and health sciences clinical medicine transplantation
- medical and health sciences clinical medicine oncology leukemia
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Coordinator
W12 0NN London
United Kingdom
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