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Genetic programming of human cell factories for the specific treatment of cancer and viral infection.

Ziel


The natural immune response to cancer and HIV is ineffective. To overcome problems of immune recognition we developed the chimerical receptor (CR) approach in which lymphocytes are redirected to efficiently eliminate desired targets. Our major objective is to optimise the CR approach towards the realisation of its clinical potential. We aim at splicing antibody and TCR-based recognition elements specific to tumours and HIV to variety of cell-activation chains and select the CR configurations yielding the most potent cells. Towards clinical application, efficient and safe retroviral and lentivirus based vectors will be developed, transduced into patient lymphocytes and tested for their ability to induce tumour regression in SCID mice. We aim to deliver vectors, protocols and optimised bioprocess to engineer a safe and efficient cell factory. Building upon our expertise and patents will allow us to launch the CR approach into clinical trials and eventually, to effective immuno-gene therapy.

Description of the work

Our groups have pioneered the CR approach for the immunotherapy of neoplastic and viral diseases. In the clinical application, patient-derived lymphocytes will be transduced with a vector harbouring CR genes composed of a target recognition moiety fused to a cell activation molecule. These genetically programmed cells upon reinfusion into the patient, are expected to home to, and lyse diseased cells. In this project, we plan to share our expertise in different disciplines and integrate it to improve and optimise the CR approach through a preclinical phase of testing in mouse models. First, we will construct a panel of CR genes using different recognition moieties enlarging the prototypic 'T body' to include variable regions of TcR, ligands for receptors overexpressed on tumours and MHC-I-peptide complexes. Each of the applicants studies distinct disease targets and our combined effort brings together expertise in prostate, breast, lymphoma, melanoma, renal, and colorectal cancers, and the viruses EBV and HIV. As activation molecules we shall employ the FcR? and TCR? chains, the CD28 co-stimulatory molecule and combinations of both. The best performing configurations will be selected. To solve a major bottleneck in operating the 'CR cell factory' one has to achieve efficient and stable expression of the CR in a short time and large number of human T cells. The expertise and facilities of Genethon for the development of retro- and lentivirus based vectors and of Got-A-Gene in targeted vectors is of great advantage towards this aim. Following the optimisation of constructs, vectors and transduction procedure, the human lymphocytes expressing CRs will be tested in SCID mice reconstituted with transduced patient-derived lymphocytes or haemopoietic stem cells. Autologous tumour explants (or HIV infected cells) will be grown in these mice. The optimal conditions to induce disease regression by autologous CR+ lymphocytes will be established in preparing the phase I clinical trials.

Milestones

Panel of functional chimeric receptor genes specific to cancer and HIV antigens
Vectors suitable for use in animals and eventual use in human therapy;
demonstration of high transduction efficacy.
Bioprocess for high and persistent expression of chimeric receptors in human
T cells
IV Tumour regression and cure of viral diseases in mouse models
Safe and active vectors for chimeric receptor gene transfer into primary human
lymphocytes

Wissenschaftliches Gebiet

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Finanzierungsplan

CSC - Cost-sharing contracts

Koordinator

WEIZMANN INSTITUTE OF SCIENCE
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Herzel Street 2
P.O.Box 26 REHOVOT
Israel

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Letzte Aktualisierung: 12 April 2005

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Permalink: https://cordis.europa.eu/project/id/QLK3-CT-1999-01262/de

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