EBMT NEWSLETTER | March 2016 | Volume 51 - Issue 2

Important dates
In 2012, Professor Chiara Bonini presented an outstanding procedure called "TCR-gene editing" allowing to generate a large number of T lymphocytes specific for a given tumor. The results of this innovative technology were published on April 2012 in the Nature Medicine journal and received the prestigious Van Bekkum Award at the 38th Annual Meeting of the EBMT in Geneva.
More recently at the Annual Meeting of the American Association for the Advancement of Science, three international leaders in the field: Professors Dirk Busch, Chiara Bonini and Stanley Riddell presented an update on new adoptive T-cell strategies for cancer.
Prof. Chiara Bonini, Head of the Experimental Hematology Unit and expert on T-cell gene therapy, San Raffaele Scientific Institute in Milan and head of the EBMT Cellular Therapy and Immunobiology Working Party, agreed to explain the TCR gene engineering technology and how it can be used as a long lasting treatment to fight cancer and infections.
What is genome editing and what we can do with this type of technology?
Chiara Bonini: Genome editing represents the most advanced frontier in the field of gene therapy. Thanks to the use of artificial molecular scissors, named nucleases, designed to cut specific gene sequences, it is today possible to disrupt selected genes in human cells, and substitute these genes with others, thus substituting, for the first time, the function of a human cell. The exploitation of this concept to cure diseases is enormous: it ranges from the possibility to substitute a mutated gene with the corrected one in stem cells, to cure genetic diseases, to the possibility to modify the genome of cells of the immune system, to cure cancer. The TCR gene editing technology was designed for this second purpose. We applied the editing technology to T lymphocytes, cells present in our body and devoted to recognize and kill pathogens, thanks to the molecule T cell receptor (TCR). Every TCR recognizes a specific pathogen, such as viruses, or bacteria. Some TCR recognize cancer cells, however, T lymphocytes expressing cancer-specific TCR are too rare to be used for cancer treatment. To overcome this limitation, we developed the TCR gene editing project. We combined the genome editing technology with gene transfer vectors and we showed that it is possible to disrupt the genes encoding for TCR in human T lymphocytes, and substitute these genes with cancer specific TCR, thus generating high number of T cells able to recognize and kill cancer cells. Such "TCR edited" lymphocytes proved effective against acute leukaemias when tested in animal models.

Could we describe T-cells as a living drug?
Chiara Bonini: yes, T-cells are living drugs and they have the potential to persist in our body for our whole lives. In a clinical trial led by Prof Fabio Ciceri, at San Raffaele and based on the infusion of donor lymphocytes genetically engineered with a suicide gene, undergoing haploidentical hematopoietic stem cell transplantation, we have tracked the presence of memory stem T-cells 14 years after the infusion into cancer patients.
How this breakthrough could pave the way for innovative treatment for leukaemia and other cancers?
Chiara Bonini: we can say that immunotherapy will join chemotherapy and radiotherapy and hematopoietic transplantation as a treatment to fight against cancer. But today, we must remember that this technology of genetically engineering cells is experimental and is tested in those rare patients with acute leukemia where standard treatments have not worked.
For example, the gene editing strategy has been used recently at Great Ormond Street Hospital in London, in a one-year-old baby girl, who had relapsed acute lymphoblastic leukaemia (ALL) and who is now cancer free. 

For more information, you can view the news briefing "Harnessing T Cells to Fight Cancer and Infection" presented at the AAAS Annual Meeting on 14 February 2016:
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