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Engineering human immunity to take on cancer

A digital illustration of a T cell attacking a cancer cell. T cells are a type of white blood cell crucial to the human immune system. © Shutterstock/ Andrea Danti
A digital illustration of a T cell attacking a cancer cell. T cells are a type of white blood cell crucial to the human immune system. © Shutterstock/ Andrea Danti

Medical researchers are using genetic engineering to revolutionise the treatment of cancer.

Developments in genetic engineering make it possible to ‘re-programme’ the human immune system so that T cells – white blood cells that normally fight viruses – recognize and kill cancer cells. This approach, which directly harnesses the potency of the immune system, holds the prospect of a powerful new weapon in the fight against cancer.

‘This is really a very different kind of treatment, with almost endless engineering possibilities unimaginable with a drug or a protein,’ said Dr Martin Pulè, of University College London (UCL), UK, who is the scientific coordinator of the EU-funded ATECT consortium. ‘These engineered cells can be thought of as highly complicated little robots.’

The way T cell therapy works is that first the cells are taken from a patient’s blood. In the laboratory, they are re-programmed by inserting synthetic genes which make them recognize cancer cells. Finally, these engineered T cells are given back to the patient intravenously. The synthetic genes instruct the T cell to make a so-called ‘chimeric antigen receptor’, a chemical hook that can make the T cell target cancerous cells.

Part of the receptor, projecting from the cell wall, is based on an antibody that can identify a cancer cell. When it encounters such a cell, the receptor activates the T cell, instructing it to attack the cancer, replicate itself and recruit other parts of the immune response to the fight.

Off-the-shelf treatment

This T cell engineering has shown huge promise for treating blood cancers, particularly where patients have suffered relapse or their cancer has not gone into remission after chemotherapy. It’s the kind of technology that could have a major impact on cancer survival in years to come, and a major focus for EU research funding. Overall, the EU said it has spent about EUR 1.1 billion on cancer research between 2007 and 2012.

‘This is really a very different kind of treatment, with almost endless engineering possibilities unimaginable with a drug or a protein.’

Dr Martin Pulè, University College London (UCL), UK

At present, the patient’s own T cells are typically used for this treatment. Consequently, the therapy needs to be tailored to each patient making it costly and impractical. In addition, some patients have insufficient T cells of their own. Partners UCL and Cellectis therapeutics within the ATECT consortium are developing a way to make an off-the-shelf T cell therapy.

Using T cells in a similar way to a blood transfusion is not straightforward, primarily because of the danger of ‘graft-versus-host disease’ where the donated T cells treat the patient’s tissues as ‘foreign’ and attack them. The only way of preventing this is to delete the T cell’s own natural antigen receptor.

While introducing new genes into T cells is well practised, until recently it has been impossible to delete existing genes with sufficient efficiency to make this possible. That’s where Cellectis therapeutics comes in. It has access to revolutionary technology called TALENs that allows highly efficient disruption of any existing gene.

Combining TALENs with chimeric antigen receptors enables the generation of off-the-shelf anti-cancer T cells. Success will lead to engineered T cell therapies that should be cheaper and more accessible, Dr Pulè said. The consortium expects to start clinical trials within the next two years, and Dr Pulè said it should take several more years for them to complete the trials and get approval to use it on patients on a general scale.

Picking the right cells 

T-CONTROL is another EU-funded project looking at T cell treatments by developing ways to sort and select immune system cells that are able to specifically attack cancer cells or germs that cause infectious diseases.

‘We’re not only working against tumours, but in addition we are trying to find pathogen- or infectious agent-specific T cells, as well as T cells that control the over-inflammation caused by the transfer of the new immune system (graft-verus-host disease),’ Professor Hermann Einsele, the coordinator of T-CONTROL, said. This will allow better control of complications in stem cell transplantation, tumour relapse, infections and graft-versus-host disease.

‘The novelty of the project is that we have methods and tools to really select T cells with a defined specificity without actually manipulating these cells,’ said Prof. Einsele, who is professor of internal medicine at the University of Würzburg, Germany.

This research could greatly improve outcomes in stem cell transplantation by helping the reconstruction of immune responses to tumours and infectious agents. It also holds out promise for treating autoimmune diseases, solid tumours and infections in patients with weakened immune systems, Prof. Einsele said.

The SUPERSIST research project, coordinated by Professor Luigi Naldini from Milan’s Universita Vita-Salute San Raffaele, is also looking at the use of haematopoietic stem cells, the blood cells that give rise to all the other blood cells, for treatment of primary immunodeficiencies and at T cells for leukaemia treatment. The consortium is working on ways to ‘edit’ the genetic make-up of haematopoietic stem cells to restore functions or fix errors in the genes. It is also looking at methods to make T cells target specific leukaemias by tailoring the T cell receptor genes that determine the specificity of these cells.

It may be some time before T cell researchers claim a decisive victory over cancer. But genetic engineering has provided new weapons, bringing hope of much more effective treatments in future. 

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