News recently came out that a baby girl has been successfully treated for a particularly aggressive form of acute lymphoblasic leukaemia (ALL) using a form of gene editing. This is only the second time that gene editing has been used in people. The first involved modifying T-cells in HIV sufferers to make them more resistant to the virus, however, which was a far lower risk strategy as these people were not at imminent risk of dying.
ALL is a cancer of one of the two types of blood cell; the “white” ones, called lymphocytes, which fight infection. They are all produced in the bone marrow; a source of those famous stem cells: these are progenitor type cells that have the potential to multiply themselves (self-renewing) and for their offspring to differentiate into more than one type of cell. In the case of ALL, the stem cells for the white blood cells start multiplying uncontrollably, releasing lots of immature “blast” cells into the bloodstream. This reduces the number of red blood cells needed to carry oxygen, and also the number of mature white blood cells, so the body’s ability to fight infection is actually reduced. Treatment usually involves a combination of radiotherapy and chemotherapy to kill the cancerous cells (these techniques kill rapidly dividing cells – a hallmark of cancer cells and the major way treatments have traditionally targetted cancer cells – I will probably provide an overview of the principles of cancer and methods used to treat it in a later post; in the meantime, here is a useful link)
Essentially, what the researchers did was to take a type of immune cells (T-cell lymphocytes) and genetically engineer them using TALEN® proteins, which act as so-called “molecular scissors”; these cut double-stranded DNA and use the cell’s own repair mechanisms to join the gap, with your gene of choice inserted. In this case, an extra gene for a receptor called CAR19 was added. A receptor, incidentally, does exactly what it says on the tin; they are proteins that sit on the outside of cells and receive proteins that act as signals. In this case the signal was in the form of another protein, called CD19, that the ALL cancer cells have on their surfaces. The T-cells (called UCART19 cells) are then programmed to seek out and destroy the cancer cells. So far, so good, and there are several human trials underway for this. But there was one major snag – ordinarily, the T-cells to be engineered are harvested from the patient’s body, engineered, and put back, but in this case the patient was too small and ill to have enough to modify. What about using T-cells from a donor then? Great, except that these cells will be recognised as not belonging to the patient’s body, and destroyed by the immune system. In fact, leukaemia patients are given drugs that essentially destroy their immune system (as it is these cells that are cancerous) and so this shouldn’t be a problem – but one of the drugs also destroys donated T-cells. So, the team, led by Prof Qasim, did something rather clever, and used the TALENs to disable a second gene in the donor T-cells, which made them invisible to this drug.
One infusion (one!) of these cells essentially cured Layla of her cancer. Later on, she was given a full bone marrow transplant as her own immune system had been destroyed by all the cancer treatment. This means, incidentally, that none of the circulating donor UCART19 cells remain. And neither, all being well, do any cancerous cells at all.
This is more than just a neat solution to a problem specific to a particular patient: it is possible (and, indeed, is the aim of the Cellectis, the company that makes them) that T-cells could be engineered such that they are suitable for anybody, and could be an off-the-shelf treatment for these types of cancer, which holds great promise for future cancer treatments.
For more on the story, read GOSH’s press release here
For more on gene editing, Wikipedia has a link here