Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS

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

Overall, the CHIMERIC EURO-CELL Consortium was extremely productive and successful. It reached most of its milestones and specific goals and in some aspects even supercede them.

Moreover and most importantly the status of the chimeric receptor approach today is significantly more closer to its realization as therapeutic modality, and due to the integrative research and concerted efforts exercised in the framework of this Consortium, the participating partners are leading the foremost front of the field world wide. Altogether we have met all the five milestones and accomplished most of deliverables put forward in our initial research plan.

The Consortium is well coordinated with efficient flow of information, ideas and materials between the collaborating partners. Each of the participating groups worked separately on various aspects of the project¿s main theme- redirection of lymphocytes - and contributes from his expertise to the concerted action. This trend is probably best reflected in the fact that the renal cancer entered into clinical trials and that the colorectal cancer project is being considered to enter this phase. In several aspects the research outcome even exceeded the workplan.

While in the first year we developed new recognition units and engineered them into an optimal receptor design, in the second and third years the development of the viral vectors and protocols to deliver the chimeric receptor genes into human T cells were accomplished and validated. Our extensive and multi-group effort to compare between vectors and to engineer and adapt them to our specific use, have yielded very significant outcome. A most important achievement made by the Rotterdam team was the development of the BULLET vector that can very efficiently transfer genes into T cells. This vector enabled us all to overcome a major technological bottle-neck in the project and achieve functional and prolonged expression of chimeric receptor genes in 40-80% of human lymphocytes.

Moreover, Partner 4 further developed the process towards the manufacture of clinical-grade vector and protocols that were found safe and were approved by the Dutch regulatory bodies for clinical trials.

Another significant development related to the gene transfer technology is the novel approach developed by Partner 6 to engineer the specificity of adenovectors to allow genetic re-targeting of this vector to any target of choice, and to cancer and T cells in the framework of this consortium. Got-A-Gene succeeded to replace the native recognition structure of adenovirus with synthetic recognition units that allow infection and gene transfer to the desired target only.

We also optimised the CR configuration so that it will cause a maximal triggering and activation of the programmed lymphocytes. A potent receptor configuration developed by Partner 1 consists of a tripartite chimera, which combines costimulation by CD28 with the stimulatory power of ITAM. An important feature of such receptor is that it avoids apoptosis resulting from over activation of T cells and it fully activate T cells.

The results obtained during this year clearly demonstrate that this receptor indeed is causing full activation of Additional important progress was made in the functional validation of genetically engineered human lymphocytes in-vivo. This has been achieved in prostate and breast cancer systems where human tumor explants in SCID mice could be specifically eliminated following administration of human T cells expressing ErbB2-specific chimeric receptors. These pre clinical experiments are very helpful in carrying the approach into the clinic. The prospective of the initiation of clinical trials within the life time of the project has became a valid option.

Reported by

Weizmann Institute of Science
Herzl str.,
76100 Rehovot
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