GOSH offers world’s first base-edited cell therapy for patients with relapsed T-cell leukemia

In a ‘bench-to-bedside’ collaboration between UCL and Great Ormond Street Hospital for Children, base-edited T cells were administered to patients with relapsed T-cell leukemia in the world’s first use of base-edited cell therapy. (Oh my goodness).

Patient Alyssa, 13 years old from Leicester, T cells Diagnosed with acute lymphoblastic leukemia (T-ALL) in 2021. She was treated with all current conventional treatments for blood cancers, including chemotherapy and a bone marrow transplant, but unfortunately her disease relapsed and she had no further treatment options.

Alyssa, the first patient to be enrolled in the TvT clinical trial, was admitted to GOSH’s bone marrow transplantation (BMT) unit in May 2022 and received pre-manufactured “universal” CAR T cells from healthy patients. I was. volunteer donor. These cells had been edited using a novel base-editing technique designed and developed by a team of researchers at UCL, led by Professor Waseem Qasim (UCL Great Ormond Street Institute of Child Health), who is also a GOSH emeritus consultant. .

Then she put on a chimera antigen Receptors (CAR) allow cancerous T cells to hunt down and kill without attacking each other.

Just 28 days later, Alyssa was in remission and underwent a second bone marrow transplant to restore her immune system. Now, six months after her BMT, she is recovering with her family at her home and continues her post-BMT follow-up at her GOSH. Without this treatment, Alyssa’s only option was palliative care.

The researchers will present the data for the first time this weekend at the American Society of Hematology annual meeting in New Orleans, USA.

The treatment of B-cell leukemia using genome-edited T cells (CAR T cells) was first performed in 2015 by the same team at GOSH and the University College London Great Ormond Street Institute for Children’s Health (UCL GOS ICH). rice field*. They recently reported on a pediatric trial using CRISPR/Cas9 technology.

But other types of leukemia are more difficult to treat this way because T cells designed to recognize and attack cancer cells also kill each other during the lab manufacturing process. Generating a bank of ‘universal’ anti-T cell CAR T cells for this study required multiple additional DNA modifications.

To generate these cells, healthy donor T cells arranged by the Anthony Nolan Registry were engineered with four separate modifications in the clean room facility of Great Ormond Street Hospital. These steps are:

1. Removing existing receptors to allow T cells from donors to be banked and used without matching – making them ‘universal’.
2. Remove a “flag” called CD7 that identifies them as T cells (CD7 T cell marker). Without this step, T cells programmed to kill T cells would simply destroy the product by ‘friendly fire’.
3. Remove the second “flag” called CD52. This makes the edited cells invisible to some of the powerful drugs administered to the patient during the treatment process.
4. Add a chimeric antigen receptor (CAR) that recognizes the CD7 T cell receptor on leukemic T cells. Cells are armed against CD7 to recognize and fight T-cell leukemia.

These edits were accomplished by ‘base editing’, chemically transforming single nucleotide bases (DNA code letters) that carry specific protein instructions. For example, changing a specific nucleotide base in the gene for CD7 from cytosine to thymine creates a “stop codon” (equivalent to a full stop in the gene) that prevents the cellular machinery from reading the full instructions and terminates CD7 production. To do.

The result is an edited CAR T cell that can be given to patients to rapidly locate and destroy T cells in the body, including leukemic T cells. If successful, patients receive bone marrow transplants to restore their depleted immune systems.

Previous treatments have relied on a technology called TALENS or CRISPR/Cas9, which produces changes in genes by molecular “scissors” cutting. The new base-editing approach works without cutting DNA, allowing more edits and less risk of unwanted chromosomal effects. This technique is also being investigated to correct deleterious changes in the DNA code of various genetic conditions.

Alyssa’s story

Alyssa was the first patient in the world to be reported to have received base-edited cell therapy and is now at home recovering from treatment. Alyssa and her family are optimistic that the leukemia has gone undetected, but they know they will have to keep a close eye on it for a while.

Thirteen-year-old Alyssa has always been at the center of decisions about her care. she said:

“I can help people by doing this because if I do it, people will somehow understand what they need to do. Of course, I will.”

Alyssa was diagnosed with T-cell leukemia in May 2021 after a long period of what her family thought was colds, viruses and general fatigue. She received standard treatment of chemotherapy and a bone marrow transplant at hospitals in Leicester and Sheffield, but unfortunately the team was unable to bring her cancer under control and into remission.

With the only other option of palliative care, Alyssa and her family have discussed this clinical trial extensively with GOSH’s bone marrow transplant and CAR T-cell therapy specialists, the first to attempt an treatment for her leukemia. decided to become a person of

Alyssa’s mother, Kiona, said:

“Doctors said the first six months were the most important and we didn’t want to be too nitpicky, but we were like, ‘If we can get it off just once, she’ll be fine.'” We kept thinking, and maybe we’re right. ”

“Alyssa is very mature and you may forget she’s just a kid, but hopefully this proves the work of the research and makes it available to more children. All of this had to be for something.Alyssa wants to go back to school but that could happen soon.Because we need to go back for the fall semester , she is already making fun of her brother.

“To be honest, we’re on weird cloud 9. It’s great to be home.”

Professor Waseem Qasim, Professor of Cell and Gene Therapy at UCL GOS ICH and Consultant Immunologist at GOSH, said:

“We have designed and developed this treatment from lab to clinic and are now testing it with children across the UK with a unique bench-to-bedside approach. This is the most sophisticated cell engineering to date, paving the way for other new treatments and ultimately for sick children. bring a better future for

We have a unique and specialized environment here at GOSH and UCL that allows us to rapidly scale new technologies, and we look forward to continuing our research and bringing it to the patients who need it most. ”

A clinical trial of this treatment has now begun and aims to recruit up to 10 T-cell leukemia patients who have exhausted all conventional treatment options. If shown to be widely successful, GOSH’s bone marrow transplant and CAR T-cell therapy team hopes to be able to offer children early in the treatment process. NHS experts are discussing and referring patients to such trials.

Dr. Robert Chiesa, GOSH bone marrow transplant and CAR T-cell therapy consultant, said:

“Alyssa has never been in complete remission since she had leukemia last May, not after chemotherapy or her first bone marrow transplant. Only after receiving a bone marrow transplant, she was free from leukemia.

“These are still preliminary results and will need to be monitored and confirmed over the coming months, but they are very noteworthy.

“The entire team here at GOSH are extremely happy with Alyssa and her family and have had the pleasure of working with them over the past few months. I am very impressed with her and nothing makes me happier than seeing her out in the open.I will be in the hospital and returning to a more normal life.”

Dr. Louise Jones, Director of Translation for the Medical Research Council, who funded the project through Pathway Funding, said:

“I am delighted to hear the promising results of this treatment and the hope it has given Alyssa and her family. Advanced gene, tissue or cell-based therapies can transform the lives of difficult people.” “Treats the disease and remains a priority for MRC. If replicated, this ‘off-the-shelf’ universal cell therapy could provide life-changing benefits to more patients. would represent a major advance in these types of treatments to provide ”

Dr. Michael Dunn, Director of Discovery Research at Wellcome, which funded the study, said:

“This is a great human example of the real-world impact of breakthrough technology and we are so proud of Alyssa and her family. It is at the core of Wellcome’s discovery research approach to transforming health and well-being.”

This trial was funded by the Medical Research Council. Support for the broader research program is also provided by Wellcome, UK Hematological Cancers, the National Institutes of Health (NIHR), and the NIHR GOSH Center for Biomedical Research.

The cell was manufactured as part of a long-standing research program led by Professor Waseem Qasim of the UCL Great Ormond Street Institute of Child Health, who is also a GOSH Honorary Consultant. Thanks to early funding from the Great Ormond Street Hospital Children’s Charity (GOSH Charity), Professor Qasim is a pioneer in the development of new his CAR T-cell therapies using innovative gene-editing techniques and has been part of the Zayed Center for Research. Based into Research into Rare Disease in Children. Partnership between GOSH and UCL GOS ICH.

The research team would like to thank Anthony Nolan for donating donor T cells and all the donors who contributed to the registry.