Designer immune cells work in a cancer test case

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Designer immune cells work in a cancer test case

Postby Marshall on November 8th, 2015, 3:25 pm ... story.html

When I accessed it the story was blocked by an ad. But the ad had a "no thanks" in very small print, it went away when I clicked "no thanks" and I was able to read the story.

It has apparently been written up in Nature journal.

Also NewSci: ... rld-first/

==excerpt NewSci==
Experimental therapy
Layla was diagnosed with acute lymphoblastic leukaemia when she was just three months old, a disease in which cancerous stem cells in the bone marrow release vast numbers of immature immune cells into the blood. She was immediately taken to Great Ormond Street to start the standard treatment of chemotherapy followed by a bone marrow transplant to restore the immune system.

In older children, this treatment is usually successful, says Sujith Samarasinghe, a leukaemia specialist at the hospital and one of Layla’s doctors. But for children as young as Layla, the cure rates are only 25 per cent.

Layla was one of the unlucky ones. Cancerous cells were still detectable after the chemotherapy. Despite this, it was decided to go ahead with a bone marrow transplant. “We hoped for a graft-versus-leukaemia reaction,” says Paul Veys, head of bone marrow transplants at the hospital. This is where immune cells in the donor bone marrow attack the cancer – but this failed too.

Gene editing saves life of girl dying from leukaemia
Within two months, Layla had relapsed. “At this stage, it is usually hopeless,” says Veys. Her parents Ashleigh and Lisa were told nothing more could be done. But they insisted the doctors did not give up. So the team emailed Waseem Qasim of University College London, who is developing a form of gene therapy to treat cancer.

Cell attack
The basic idea is to remove immune cells from a patient’s body, genetically engineer them to attack cancerous cells and place them back in the body. Several human trials are already underway around world. Some trials involve adding a gene for a receptor called CAR19, which sits on the outside of the T-cells. This programs the T-cells to seek out and kill any cells with a protein called CD19 on their surface – which is found on the cells that cause acute lymphoblastic leukaemia.

But engineering bespoke T-cells for every cancer patient is not cheap. And in Layla’s case, it would not have worked because she didn’t have enough T-cells left to modify. “She was too small and too sick,” says Qasim.

Qasim’s team, however, has been developing “off-the-shelf” treatments, in which T-cells from a healthy donor are modified so they could potentially be given to hundreds of patients. Normally if T-cells from another person were injected into a recipient who was not a perfect match, they would recognise all of the recipient’s cells as foreign and attack them. To prevent this, Qasim’s team used gene editing to disable a gene in the donor cells that makes a receptor that recognises other cells as foreign.

Molecular scissors
Conventional gene therapy can only be used to add genes to DNA. But with gene editing, specific DNA sequences can be cut with “molecular scissors”, introducing mutations that disable a particular gene. Qasim’s molecular scissors were of a kind known as TALEN proteins.

But there was still another problem to overcome. The recipient’s immune system also recognises non-matched T-cells as foreign and will attack them. In leukaemia patients, this is not a problem because they are given drugs that destroy their immune system. Except, one of these drugs – an antibody – also destroys donor T-cells. So Qasim’s team also disabled a second gene in the donor T-cells, which made them invisible to the antibody.

At the time that Qasim was contacted by Layla’s doctors, his engineered T-cells, called UCART19 cells and developed in collaboration with New York biotech company Cellectis, had only ever been tested in mice. “It was scary to think the treatment had never been used in a human before,” said Layla’s father Ashleigh, “but there was no doubt we wanted to try the treatment. She was sick and in lots of pain, so we had to do something.” And it worked within weeks.

This is only the second time that gene-edited cells have been used in people. The first ever trial involved modifying T-cells in people with HIV to make them more resistant to the virus, although these participants were not in immediate danger of dying.

Chop and change
The molecular scissors used to disable genes do sometimes make cuts in the wrong place, which carries a small risk of causing adverse effects such as turning cells cancerous.

But after three months, Layla was given a second bone marrow transplant to restore her immune system. These healthy immune cells recognised the UCART19 cells as foreign and destroyed them, so Layla no longer has any genetically modified cells in her body.

Layla will continue to have regular tests until her doctors are sure the cancer is gone. “It is too early to say she is cured,” says Samarasinghe, but she is alive and well.

Cellectis plans to start full clinical trials early in 2016. Qasim says other patients in the UK are already being treated with these cells, although he would not reveal any details. The team will present the case study at the American Society of Hematology meeting in Florida in December.

We will have to wait for the results of those trials to be sure this was not a one-off, but if they are successful, it would be a huge step forward for treating leukaemia and other cancers, Qasim says. “It’s incredibly encouraging,” he says. “There are a whole bunch of other disorders we can now create fixes for.”

Image credits: Top image: Sharon Lees/GOSH; Second image: GOSH

By Michael Le Page
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Re: Designer immune cells work in a cancer test case

Postby Marshall on November 8th, 2015, 3:44 pm 

Press release from "Great Ormond Street Hospital for Children" GOSH, in the UK ... -leukaemia

This seems reasonably informative, and at least is easy to access.

==excerpt from press release==

World first use of gene-edited immune cells to treat ‘incurable’ leukaemia

05 November 2015


The treatment works by adding new genes to healthy donor T-cells, which arm them against leukaemia. Using molecular tools (TALEN®) that act like very accurate scissors, specific genes are then cut in order to make the T-cells behave in two specific ways. Firstly, the cells became invisible to a powerful leukaemia drug that would usually kill them and secondly they are reprogrammed to only target and fight against leukaemia cells.

The team at GOSH and the UCL ICH, along with investigators at University College London and biotech company Cellectis, had been developing ‘off-the-shelf’ banks of these donor T-cells and the first of which was due to be used for final stage testing ahead of clinical trials. But, after hearing about this infant, the team received special permission to try the new treatment early.

Professor Waseem Qasim, Professor of Cell and Gene Therapy at UCL ICH and Consultant Immunologist at GOSH, explains: "The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought ‘why don’t we use the new UCART19 cells?’

"The treatment was highly experimental and we had to get special permissions, but she appeared ideally suited for this type of approach."

The patient’s parents were also keen to try the treatment. Mum, Lisa, says: "We didn’t want to accept palliative care and so we asked the doctors to try anything for our daughter, even if it hadn’t been tried before."

The treatment consisted of 1ml of UCART19 cells delivered via intravenous line in around 10 minutes. After the cells had been delivered, the patient spent several months in isolation to protect her from infections while her immune system was extremely weak. Throughout this time, the patient stayed generally well.

After several weeks there were signs that the treatment was working. Professor Paul Veys, Director of bone marrow transplant at GOSH and the patient’s lead clinician, says: "As this was the first time that the treatment had been used, we didn’t know if or when it would work and so we were over the moon when it did. Her leukaemia was so aggressive that such a response is almost a miracle."

Once doctors were confident that the leukaemia cells had been removed, the patient was given a bone marrow transplant to replace her entire blood and immune system which had been wiped out by the treatment. The child is now recovering well at home, although she returns to GOSH regularly to check that her bone marrow cells are healthy and blood counts continuing to normalise.

Professor Qasim says: "We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children. But, this is a landmark in the use of new gene engineering technology and the effects for this child have been staggering.

"If replicated, it could represent a huge step forward in treating leukaemia and other cancers."

Full clinical trials funded by Cellectis are now being planned to test UCART19 cells in larger groups of patients and are set to begin early in 2016.

“Cellectis main objective is to provide cancer patients with an accessible, cost-effective, off-the-shelf allogeneic CAR-T therapies across all geographies. With clinical trial for the first gene-edited UCART on the horizon, it could be the beginning of a revolution in cancer immunotherapy,” says Dr. André Choulika, Chairman and CEO of Collects.

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Re: Designer immune cells work in a cancer test case

Postby wolfhnd on November 8th, 2015, 11:02 pm 

This represents a level of medical sophistication I never expected to see in my lifetime.

We may need to have a discussion on the ethical issue concerning who get these new "miracle" cures.
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