Brave new therapy
MSS Murthy Dec 8, 2015
During the first week of November 2015, many science journals and magazines across the globe flashed the photograph of a smiling one-year-old girl. Reason? Doctors from the Great Ormond Street Hospital, London, had achieved remission in the little girl’s leukaemia, with a never before used treatment, using genetically engineered donor T cells.
Layla Richards was diagnosed with acute lymphoblastic leukaemia (a B-cell malignancy) when she was just three-months-old — a disease in which cancerous stem cells from bone marrow release vast number of immature immune B-cells into the blood. Doctors had tried all the established procedures like chemotherapy and bone marrow transplant — but without much success. In such a case the normal procedure would be to treat leukaemia using the patient’s own T cells modified in such a way to attack and kill the cancer cells, which would otherwise escape immune detection.
T cells or T lymphocytes (a type of white blood cells) circulating in the blood play a crucial role in cell-mediated immunity. A unique feature of these cells is their ability to distinguish between self and non-self (like transplanted donor cells) and between normal and abnormal cells (like infected cells and cancerous cells) through an antigen receptor known as “T cell receptor” (TCR) on their surface.
They bind to the specific antigens on the surface of such cells and destroy them. So, when other methods are unsuccessful, doctors extract the patient’s own blood and separate the T cells. To make them hunt for any specific type of cancer cells, they have to have on their surface, a chimeric antigen receptor (CAR), which can recognise cancer-specific antigens. To achieve this, the patient’s T cells are first treated with a disabled virus carrying a synthetic gene code for such an antigen receptor.
When the virus infects the T cell, it does not do any harm to the cells, but transfers the synthetic gene to the T cell genome, thus enabling them to express the CAR. Such modified cells are multiplied through cell culture techniques in the laboratory and then put back in large numbers to the patient’s body. These cells, known as Chimeric Antigen Receptor T cells (CART-cells), not only bind to the cancer cells and destroy them, but also start multiplying, creating a cancer killing army inside the body.
Unfortunately, the procedure could not be used in the case of Layla. Because chemotherapy had obliterated her immune system and no T cells were left. Just before Layla’s first birthday, the disease had reached end stage and doctors could only advise her family to go for palliative care. But her parents would not take it. “We did not want to give up on our daughter, though. So we asked doctors to try anything,” her mother Lisa said. The solution came in the form of genetically engineered T-cells from a donor.
Professor Waseem Quasim, University College, London, in collaboration with Cellectis, a biotech company in Paris has been developing “off-the-shelf” treatments in which T cells from healthy donors are so modified that they could be given to any patient without worrying about matching problems — the universal T cells. Normally, if T cells from a person are injected into a recipient, who is not a perfect match, they would recognise the recipient’s cells as foreign and attack them, leading to graft-versus-host reaction.
To prevent this, the researchers used a gene-editing tool known as Transcription Activator-like Effector Nuclease (TALEN) to knockout the TCR alpha gene. This would eliminate the TCR expression and abrogate the donor T-cell’s potential for graft-versus-host disease. Next, they knocked out another gene called CD52 to protect the donor T cells from being destroyed by the anti-cancer drugs the patient was receiving. Finally, just as in autologous T cell therapy, they introduced a new gene into the donor T cell to produce a protein called CAR 19 to target the antigen CD 19, which is present on the surface of the cancer cells. With CAR 19 on their surface, the engineered T cells would aggressively seek and destroy not only the cancer cells but also the stem cells that generate them.
These engineered T cells known as Universal CART 19 cells (UCART 19 cells) were not yet clinically tested for their efficacy and safety. Still, when faced with a compassionate situation as in the case of little Layla, doctors consented to treat her after obtaining permission from the concerned authorities. Layla was given an injection of UCART 19 cells (4.5X 106 cells per kg body weight) in June. Doctors kept their fingers crossed. But, miraculously, within weeks after treatment, her condition improved. After three months, she received a bone marrow transplant to boost her own immune system. By November, doctors attending on her announced that her leukaemia was under remission.
The journal New Scientist, on November 5, 2015 announced, “Gene editing saves girl dying from leukaemia in the world first.” Layla’s father Ashleigh Richards said, “And this is her day — standing, laughing, and giggling. She was so sick before this treatment, it was horrible and I am just thankful for this opportunity.”
However, the team treating Layla cautioned during a press conference that it is too soon to say if Layla has been cured. The only way they can find out if this is a cure is by waiting for one or two years. Meanwhile, Professor Waseem opines that the TALEN engineered universal CART 19 cells have provided an “early proof-of-concept evidence for ready-made T cell strategy” and plans safety trials next year with 10 to 12 patients. If all goes as planned, he says that this technique can become a treatment of choice for a number of haematological cancers and other diseases.
Layla Richards was diagnosed with acute lymphoblastic leukaemia (a B-cell malignancy) when she was just three-months-old — a disease in which cancerous stem cells from bone marrow release vast number of immature immune B-cells into the blood. Doctors had tried all the established procedures like chemotherapy and bone marrow transplant — but without much success. In such a case the normal procedure would be to treat leukaemia using the patient’s own T cells modified in such a way to attack and kill the cancer cells, which would otherwise escape immune detection.
T cells or T lymphocytes (a type of white blood cells) circulating in the blood play a crucial role in cell-mediated immunity. A unique feature of these cells is their ability to distinguish between self and non-self (like transplanted donor cells) and between normal and abnormal cells (like infected cells and cancerous cells) through an antigen receptor known as “T cell receptor” (TCR) on their surface.
They bind to the specific antigens on the surface of such cells and destroy them. So, when other methods are unsuccessful, doctors extract the patient’s own blood and separate the T cells. To make them hunt for any specific type of cancer cells, they have to have on their surface, a chimeric antigen receptor (CAR), which can recognise cancer-specific antigens. To achieve this, the patient’s T cells are first treated with a disabled virus carrying a synthetic gene code for such an antigen receptor.
When the virus infects the T cell, it does not do any harm to the cells, but transfers the synthetic gene to the T cell genome, thus enabling them to express the CAR. Such modified cells are multiplied through cell culture techniques in the laboratory and then put back in large numbers to the patient’s body. These cells, known as Chimeric Antigen Receptor T cells (CART-cells), not only bind to the cancer cells and destroy them, but also start multiplying, creating a cancer killing army inside the body.
Unfortunately, the procedure could not be used in the case of Layla. Because chemotherapy had obliterated her immune system and no T cells were left. Just before Layla’s first birthday, the disease had reached end stage and doctors could only advise her family to go for palliative care. But her parents would not take it. “We did not want to give up on our daughter, though. So we asked doctors to try anything,” her mother Lisa said. The solution came in the form of genetically engineered T-cells from a donor.
Professor Waseem Quasim, University College, London, in collaboration with Cellectis, a biotech company in Paris has been developing “off-the-shelf” treatments in which T cells from healthy donors are so modified that they could be given to any patient without worrying about matching problems — the universal T cells. Normally, if T cells from a person are injected into a recipient, who is not a perfect match, they would recognise the recipient’s cells as foreign and attack them, leading to graft-versus-host reaction.
To prevent this, the researchers used a gene-editing tool known as Transcription Activator-like Effector Nuclease (TALEN) to knockout the TCR alpha gene. This would eliminate the TCR expression and abrogate the donor T-cell’s potential for graft-versus-host disease. Next, they knocked out another gene called CD52 to protect the donor T cells from being destroyed by the anti-cancer drugs the patient was receiving. Finally, just as in autologous T cell therapy, they introduced a new gene into the donor T cell to produce a protein called CAR 19 to target the antigen CD 19, which is present on the surface of the cancer cells. With CAR 19 on their surface, the engineered T cells would aggressively seek and destroy not only the cancer cells but also the stem cells that generate them.
These engineered T cells known as Universal CART 19 cells (UCART 19 cells) were not yet clinically tested for their efficacy and safety. Still, when faced with a compassionate situation as in the case of little Layla, doctors consented to treat her after obtaining permission from the concerned authorities. Layla was given an injection of UCART 19 cells (4.5X 106 cells per kg body weight) in June. Doctors kept their fingers crossed. But, miraculously, within weeks after treatment, her condition improved. After three months, she received a bone marrow transplant to boost her own immune system. By November, doctors attending on her announced that her leukaemia was under remission.
The journal New Scientist, on November 5, 2015 announced, “Gene editing saves girl dying from leukaemia in the world first.” Layla’s father Ashleigh Richards said, “And this is her day — standing, laughing, and giggling. She was so sick before this treatment, it was horrible and I am just thankful for this opportunity.”
However, the team treating Layla cautioned during a press conference that it is too soon to say if Layla has been cured. The only way they can find out if this is a cure is by waiting for one or two years. Meanwhile, Professor Waseem opines that the TALEN engineered universal CART 19 cells have provided an “early proof-of-concept evidence for ready-made T cell strategy” and plans safety trials next year with 10 to 12 patients. If all goes as planned, he says that this technique can become a treatment of choice for a number of haematological cancers and other diseases.
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