TT52CAR19 therapy for B-cell Acute Lymphoblastic Leukaemia (B-ALL)v3.2
Research type
Research Study
Full title
Phase 1 , open label study of CRISPR-CAR genome edited T cells (TT52CAR19) in relapsed /refractory B Cell Acute Lymphoblastic Leukaemia
IRAS ID
268395
Contact name
Waseem Qasim
Contact email
Sponsor organisation
Great Ormond Street Hospital for Children NHS Trust
Eudract number
2019-003462-40
Clinicaltrials.gov Identifier
Duration of Study in the UK
3 years, 0 months, 0 days
Research summary
Research Summary:
This trial is designed for children whose B-cell Acute Lymphoblastic Leukaemia has returned and who have exhausted routine treatment options. We propose to use a cell product called PBLTT52CAR19 made of T-cells (a type of white blood cells involved in fighting infections) genetically engineered to fight leukaemia.
These T-cells come from a healthy donor and have been modified in several ways. A receptor was added to help the TTCAR19 cells recognise a marker (flag) on the B leukaemia cells and attach to them, leading to the death of the leukaemia cell. Other changes include removing flags present on the T-cell surface in order to reduce the chances that the patient’s own immune cells recognise and kill these donor PBLTT52CAR19 cells.
The aim of this study is to test the safety of PBLTT52CAR19 therapy and see if it can eliminate leukaemia to allow a bone marrow transplant that will hopefully prevent the leukaemia from returning. Up to 10 patients will be included in this trial that will take place at Great Ormond Street Hospital.
Patients will undergo careful screening to confirm that this treatment is adequate for them. If they join the study, we will need to wipe out their existing immune system with chemotherapy prior to PBLTT52CAR19 infusion, as past research indicates that this improves the ability of T-cells to establish and grow. Patients will then receive a single infusion of PBLTT52CAR19 cells. They will be closely monitored via blood and bone marrow tests for safety and to check the levels of PBLTT52CAR19 and leukaemia cells. We expect patients to be in hospital for a minimum of 2 weeks, and likely 4 weeks for the PBLTT52CAR19 therapy. The transplant will be scheduled 2-4 weeks after the end of PBLTT52CAR19 if leukaemia cells are no longer detectable. Patients will be monitored for 3 years.Lay summary of study results:
This study explored an innovative treatment for children with a severe form of blood cancer called relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL). When standard therapies fail, the options for children with this disease are very limited, leading to poor outcomes. This research trial tested a new approach using immune cells (T cells) that are modified in the lab using a groundbreaking technology called CRISPR-Cas9. The aim was to see if this new treatment could be effective, safe, and practical for children who desperately need better options.
What is this study about?
Leukemia is a cancer of the blood and bone marrow, and B-ALL is one of the most common types in children. While most children with leukemia respond well to treatment, some experience a relapse (the disease returns) or do not respond to initial treatments. These cases are described as “refractory.” Existing therapies, such as personalised immune treatments (CAR T cell therapy), can be effective but have major limitations, including long preparation times and high costs, which make them unavailable to many patients.
The treatment tested in this study, called TT52CAR19, aims to address these barriers. It uses T cells donated by healthy individuals, which are then modified in the lab to recognize and attack leukemia cells. The researchers used CRISPR-Cas9, a cutting-edge gene-editing tool, to improve the T cells, making them universally compatible with any patient and more effective at surviving in the body. These pre-prepared T cells could allow for faster and more accessible treatment compared to personalized approaches.
What did the researchers do?
The study treated seven children aged 6 months to 18 years with relapsed or refractory B-ALL. All participants had very few options left after trying other treatments. These children received the TT52CAR19 treatment as part of a carefully designed process:
1. Preparation: Before receiving the treatment, the children underwent a procedure called lymphodepletion, where medications were used to temporarily weaken their immune systems. This step helps the modified T cells survive and work better in the body.
2. T Cell Infusion: Each child received a single dose of the CRISPR-edited T cells.
3. Monitoring: Over the next 28 days, the researchers closely monitored the children’s health and measured how the T cells behaved in their bodies, including how well they fought the leukemia.
The researchers also tracked side effects to ensure the treatment was safe. After the 28-day period, children who responded well to the therapy underwent a bone marrow transplant to help secure long-term remission.What did the study find?
The results showed encouraging signs, but with some limitations:
Effectiveness: Four out of 7 children has no detectable leukemia (in remission) after 28 days of treatment. This means the TT52CAR19 cells successfully targeted and killed the cancer cells in these children. These four were then able to receive a bone marrow transplant, to rebuild their immune systems. Two successfully completed BMT are in long term remission Three children did not respond to the treatment sufficiently to get to BMT Side/Adverse Effects: Most side effects were mild to moderate and expected based on similar treatments. These included fever, inflammation, and changes in blood counts.
Two children experienced more severe side effects: one had temporary neurotoxicity (seizures), and another developed a mild skin rash linked to immune activity. Both recovered with treatment.
Safety: The study showed that the treatment is feasible and can be given with manageable risks.Why is this research important?
This study is one of the first to use CRISPR gene-editing technology to modify immune cells for treating children with leukemia. The approach offers several potential advantages:
1. Faster and More Accessible: The T cells can be prepared in advance and stored, meaning they are ready to use when a patient needs them. This could reduce delays, which are critical for children with aggressive cancer.
2. Universal Compatibility: Unlike current CAR T cell therapies, which require cells to be collected and modified from each individual patient, TT52CAR19 uses donor cells that can be given to any child.
3. Promising Results: The trial dosed 7children, and strong anti-leukaemia activity in four of them suggests that this treatment could provide valuable options where there are no alternatives.What are the limitations of the study?
This was an early-stage trial (Phase 1), so the main focus was to assess safety and feasibility rather than long-term effectiveness. The small number of participants means more research is needed to confirm these findings and understand why some children did not respond.In summary, this study provides early evidence that CRISPR-edited immune cells could be a safe and effective option for treating children with difficult-to-treat leukemia. While further research is needed, it represents a significant step forward in the search for new treatments that are faster, more accessible, and potentially lifesaving.
For more information and to read the full scientific paper, please visit: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fwww.researchgate.net%252Fpublication%252F356485283_TT52CAR19_Phase_1_Trial_of_CRISPRCas9_Edited_Allogeneic_CAR19_T_Cells_for_Paediatric_RelapsedRefractory_B-ALL%2FNBTI%2FYGC6AQ%2FAQ%2F266445e4-2ce4-43bb-a209-880214f37d1e%2F1%2FR2wgv6Iva_&data=05%7C02%7Cwestlondon.rec%40hra.nhs.uk%7C229691b3d4d64ac13dc908dd2936ef68%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638712038085687152%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=lv94fqUp6XZMGnB0QHio54LZ64fzx0KtcH%2BaQ6xLe0g%3D&reserved=0 or visit the clinical trial registry at NCT04557436. You can also contact the research team at Great Ormond Street Hospital for additional details.
We want to express our deepest gratitude to the children and families who participated in this important study. Without your courage and contribution, advancements like this would not be possible.REC name
London - West London & GTAC Research Ethics Committee
REC reference
19/LO/1767
Date of REC Opinion
30 Mar 2020
REC opinion
Further Information Favourable Opinion