Gene Therapy Cure for Childhood Cancer

It has been over a decade since the first draft of the human genome was completed. I was in my final year studying genetics and it seemed like it was only a matter of time until we had a cure for everything from cancer to cystic fibrosis. As you may have noticed, progress has not been quite that swift. Whilst we do, every day, push back the boundaries of our knowledge of the genome, finding out precisely how our 22,000 genes are switched on and off, how they in turn produce the million or so proteins our bodies are made up of, and then how each of those million proteins interact to create a healthy human being is a fiendishly complicated task. We are not, then, quite at the stage where we can wave our medical wands and cure whatever ails you, but every now and then something comes along which feels like a real step forward. Recently I talked about a new treatment for Huntington’s Disease, today it is a really quite clever treatment for leukaemia.

Teams at Great Ormond Street Hospital and the Institute for Child Health (I can see both of these buildings from my desk, we’re on the same block) have used a gene editing technique known as TALENs to modify T cells so that they would attack cancer cells without harming the patient’s own cells. T cells are a type of lymphocyte, lymphocytes being a type of white blood cell, that are a crucial component of our immune system. The patient, in this case was a little girl called Layla, she was only 1 year old when treatment began. Layla had acute lymphoblastic leukaemia (ALL), an aggressive form of cancer that causes the bone marrow to release immature B cells into your blood stream. This causes a decrease in the number of red blood cells and platelets and also severely compromises the immune system. ALL is the most common form of cancer in children affecting 1 in 2000, fortunately the prognosis is generally good, most will survive; unfortunately, in Layla’s case her cancer had come back even after treatment and a bone marrow transplant.

Her medical team then embarked upon a never before tried therapy. Having obtained special ethical approval and the informed consent of the parents they set to work developing a potentially curative genetic treatment. The immature B cells that Layla was inadvertently producing are covered in the antigen known as CD19, an antigen being the molecular marker on the outside of a cell that identifies it as a particular cell type in a particular organism, sort of like a little name badge. The team engineered a chimeric type of T cell that specifically hunted down and killed any cell carrying the CD19 antigen.

They did this using a type of molecular scissors known as TALENs, transcription activator-like effector nucleases. Genetics is full of simple sounding phrases like this but the take home message is that the system uses a pair of molecules; one of them recognises a specific point in the genome and the other one makes a cut in the DNA at that precise point.

Using TALENs to make their B cell-hunting T cells was only the beginning of the challenge, though. Normally these cells would have been derived from the patient’s own ones to stop them being rejected and also to stop the new cells attacking the whole of their new foreign host, but Layla’s bone marrow had been destroyed and replaced by that of a donor so the doctors had to get creative. T cells recognise other cells as either foreign or self via a receptor molecule on their surface called the T cell receptor alpha chain. Using TALENs the team made a cut in the DNA that encodes this gene, this stops it being expressed and the protein is no longer produced thereby removing the cell’s ability to recognise cells as foreign or self. But that was only half the problem.

To stop Layla’s body from destroying the invading T cells they once again deployed the TALENs system. This time they used it to make a cut in the CD52 gene, this encodes the CD52 antigen which is only present on mature lymphocytes. By destroying this the team effectively made a stealth cloak for the cells which rendered them  unrecognisable to Layla’s immune system.

The treatment was administered this past summer and so far the results are very encouraging, Layla is getting better. We still need to be cautious, though, as an analysis of her bone marrow shows that 3% of it is still her own and this means that there is a chance the cancer could still come back but her doctors are hopeful. All we can do at this stage is wait and see how she does in the long term.

Progress in the realm of gene therapies has not been as fast as anyone wanted, but here we can see a concrete example of a potential treatment for many children all over the world. One of it’s appeals is that it is an off the shelf option, this could be used in anyone without the need to tailor it to an individual’s circumstances; that’s a massive plus. As this was a special, one off case the next step is a proper clinical trial in multiple people to fully test the efficacy of the treatment. In the meantime let’s take a moment to marvel that we as a species can engineer a stealth cell capable of selectively hunting out and destroying our own faulty cells. Good job, science.

A scanning electron micrograph of a healthy human T cell
A scanning electron micrograph of a healthy human T cell

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