CAR T cells for T cell cancers

Plain English summary of protocol

Background and study aims
T-cell Acute Lymphoblastic Leukaemia (T-ALL) and T-cell Lymphoblastic Lymphoma (T-LBL) are aggressive cancers that are hard to cure. Often, the cancer does not respond to treatment or comes back afterwards. For these patients, treatment options are limited and usually involve intensive chemotherapy followed by a stem cell transplant. However, chemotherapy often fails, and many patients are too unwell for a transplant. Even when possible, transplants carry serious risks and long-term side effects. There is an urgent need for safer, more effective therapies.
This study is testing a new product called CAR-T cells (short for Chimeric Antigen Receptor T cells) in patients with T-ALL or T-LBL whose disease has not responded to treatment or has returned after initial success. T cells are part of the immune system and help fight infections. In CAR-T therapy, we take a patient’s own T cells and modify them in the lab so they can recognise and kill cancer cells. These reprogrammed cells are called CAR-T cells. CAR-T cells have already shown success in another type of leukaemia called B-ALL, leading to long-term remissions in many patients. There is growing evidence that CAR-T therapy may also work in T-ALL and T-LBL.
In this study, we are developing a new type of CAR-T cell that targets a marker called CCR9, found on most cancerous T cells. We will collect T cells from each patient’s blood, modify them to recognise CCR9, and then give them back to the patient. The main goals of the study are to find out if these new CAR T cells are safe and to determine the best dose. We plan to give the cells to 12 children (under 18) and 12 adults.

Who can participate?
Patients with relapsed or refractory T-ALL/T-LBL following at least one or two standard prior lines of combination cytotoxic therapy

What does the study involve?
Patients will receive a short course of chemotherapy before getting the CAR-T cells, which are given through a drip. They will stay in hospital for at least 2 weeks and be closely monitored. After leaving hospital, they will return for regular check-ups for two years, including blood tests, scans, and sometimes bone marrow tests.

What are the possible benefits and risks of participating?
Leukapheresis is required to collect the patient’s T cells from the blood for the manufacture of CAR-T cells. The T cells are collected using a central line or a small plastic tube inserted into a large vein. Depending on the participant’s age and health condition, they may have a general anaesthetic or a local anaesthetic applied to the skin before the line insertion. Pain, bruising and a small amount of bleeding can occur around the insertion site. Pain medication and application of a pressure dressing will be used if needed. The small risk of fainting will be prevented by having the patient sit or lie down during the procedure. Muscle cramps can be prevented by taking calcium supplements if needed.
The chemotherapy proposed is based on the regimen used in the commercially available anti-CD19 CAR for B-ALL, tisagenlecleucel. This has also been the most-used regimen in studies of anti-CD7 CAR-T in T-ALL. Fludarabine is generally well tolerated: the most common side effects are lymphopenia and infection. Neurotoxicity can occur but this is generally only observed in higher doses. Cyclophosphamide can cause bleeding from the bladder. Cardiotoxicity can occur but is extremely rare at the proposed dose. Cyclophosphamide may cause transient nausea and cytopenias. Participants will be monitored, and appropriate supportive care will be instituted as necessary. Participants will be given anti-emetic prophylaxis, transfusion support and antibiotics as required as per standard institutional policy.
Cytokine release syndrome (CRS) occurs to some extent in most CAR-T cell therapies. In studies of CD7 targeting CAR T cells, the most widely studied antigen in T-ALL, 60-90% of patients treated developed CRS of any grade, but severe CRS only occurred in 10-18% of all patients and appeared to relate to disease burden. CRS is characterised by culture-negative fever and/or hypotension, hypoxia, and neurological disturbance and appears to be mediated by hypersecretion of pro-inflammatory cytokines, particularly IL-6 and IFN-γ. Severe CRS often requires high-dependency supportive care and is usually self-limiting but may be fatal. Diagnostic criteria for severe CRS have now been established, and treatment with the IL-6 receptor-blocking antibody tocilizumab appears to be highly effective. A number of other agents are clinically available to investigators for the management of CRS that is unresponsive to tocilizumab. Patients enrolled will need to be of relatively good health and thus likely to be able to withstand the potential toxicity of CAR-T cell therapy. Patients will be monitored for a period of 28 days after CARCCR9 T cell infusion with daily clinical review and blood tests, including C-reactive protein (CRP). In the event of a cytokine-driven serious adverse event (SAE) occurring, the trial site has facilities for resuscitation and intensive care. Patients developing CRS will receive supportive care including intravenous fluids, intravenous antibiotics (pending cultures), supplementary oxygen and if needed, ventilatory/inotropic support in the intensive care unit.
Neurotoxicity, termed Immune effector cell associated neurotoxicity syndrome (ICANS), is well described in patients treated with other CAR T cell therapies and is of variable severity. Severe ICANS has an approximate incidence of 1-21% in CD19-targeting CAR-T cell therapy. In T-ALL, rates of ICANS in CD7 CAR-T trials have been low (1-15%) and of low grade. Most neurotoxicity is mild and transient and resolves spontaneously, but more severe cases can present with aphasia, obtundation, delirium and seizures and may require supportive treatment with anticonvulsants, corticosteroids, and in some cases, sedation and ventilation. In rare cases fatalities have been reported. On FRACTALL, participants developing neurotoxicity will receive clinical investigations and supportive care as per standard institutional policy and all participants with neurotoxicity should be discussed with the CI and TMG. Decisions regarding corticosteroids or other immunosuppressive therapy should be discussed with the CI/TMG.
Lymphodepletion may cause a drop in blood cell count and recovery may be delayed by the CAR T cells. Participants will have blood counts monitored and will be given blood product transfusions and supportive medication if needed.
The low blood cell count may increase the chance of participants getting an infection. As a precaution, participants will be given antibiotics and antivirals. Participants will be monitored for signs of infection and given appropriate medication if needed.
Participants will be admitted to hospital or ambulatory care while having pre-conditioning lymphodepletion and for a minimum of 2 weeks following CARCCR9 T cell infusion. Afterwards, participants will have regular follow-up visits in clinic for 2 years. These visits are comparable to those following alternative therapies such as stem cell transplants.

Where is the study run from?
Cancer Research UK & University College London Cancer Trials Centre (UK)

When is the study starting and how long is it expected to run for?
April 2025 to December 2035

Who is funding the study?
1. Medical Research Council (UK)
2. Great Ormond Street Hospital Children's Charity (UK)

Who is the main contact?
FRACTALL Trial Manager, ctc.fractall@ucl.ac.uk

Plain English summary under review with external organisation

Contact information

Study information

Eligibility

Locations

Countries of recruitment

• United Kingdom

Study participating centre

Sponsor information

University College London
Hospital/treatment centre

Cancer Research UK & University College London Cancer Trials Centre
90 Tottenham Court Road
London
W1T 4TJ
England
United Kingdom

Phone	+44 (0)20 76705748
Email	ctc.FRACTALL@ucl.ac.uk
Website	http://www.ucl.ac.uk/
"ROR"	https://ror.org/02jx3x895

Funders

Funder type

Research council

Results and Publications

Editorial Notes

16/07/2025: ISRCTN received notification of combined HRA/MHRA approval for this trial on 16/07/2025.
24/04/2025: Study's existence confirmed by the HRA.