Autologous chimeric antigen receptor T cells targeting CCR9 for the treatment of T acute lymphoblastic leukaemia

Lead Research Organisation: University College London
Department Name: Haematology


T cell acute lymphoblastic leukaemia (T-ALL for short) is a rare type of acute leukaemia. About half of patients with T-ALL can be successfully treated with chemotherapy. However, there are no effective treatments for patients whose disease remains after chemotherapy or which comes back after treatment.

Recently, a new type of cancer treatment called "Chimeric Antigen Receptor T cell therapy" or "CAR-T cell therapy" for short, has been developed. T cells are cells from our immune system. Their job is to move around our bodies finding and killing cells infected with a virus. CAR-T cells are T cells taken from a patient's blood and "re-programmed" using genetic engineering so that they recognise cancer cells. When returned to the patient in a drip, they live and grow within the patient,finding and killing cancer cells.

CAR-T cell therapy works well in patients with certain cancers including a common type of acute leukemia, but has not been used in T-ALL. This is because T-ALL is a leukaemia which develops from normal T cells. CAR-T cells which recognise any T cell would end up killing themselves or killing normal T cells, without which a patient would quickly suffer from severe infections.

We have found that a protein called CCR9 is only found in leukaemia T cells. We have developed CAR-T cells which recognise CCR9. CCR9 CAR-T cells kill T-ALL cells but do not recognise normal T cells. We propose to test CCR9 CAR-T cells in an an initial clinical study in patients with incurable T-ALL. If CCR9 CAR-T cells work well in the clinical study, this would be the first step in making CCR9 CAR-T cells more widely available for patients with T-ALL.

Technical Summary

T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy of immature T cells. While approximately half of adults with T-ALL can be cured with conventional therapy, relapsed and refractory (r/r) disease carries a poor prognosis. There is no standard of care, and most patients receive intensive salvage chemotherapy with a view to allogeneic haematopoietic stem cell transplant (allo-HSCT). This treatment pathway is highly toxic and rarely successful, with long-term survival <10%. No promising new treatments are available for T-ALL. By contrast, chimeric antigen receptor (CAR)-T cell therapy is revolutionising the treatment of patients with r/r B cell ALL (B-ALL), a closely related disorder. Here, many patients have durable responses after CAR-T. Replicating this success in T-ALL has thus far proven difficult. In B-ALL, pan-B cell antigens (like CD19) can be targeted by CAR-T, since the concomitant normal B cell aplasia is clinically tolerable. An analogous approach in T-ALL, resulting in targeting of normal T cells, faces two problems. Firstly, the CAR-T cells would target each other (so-called fratricide); if this problem could be overcome, depletion of the normal T cell compartment would lead to unacceptable immunosuppression. Absent to date is a target expressed on T-ALL but not on normal T-cells. We have identified such an antigen, demonstrating that C-C chemokine receptor type 9 (CCR9) is expressed on ~85% of cases of r/r T-ALL, with expression on normal tissues limited to <5% of normal immune cells. We have developed anti-CCR9 CAR-T cells and shown potent anti-leukaemic activity in vitro and in vivo, using cell line models and patient-derived xenografts. We hypothesise that anti-CCR9 CAR-T cells is a safe and effective treatment strategy for T-ALL and propose a phase-1 first-in-human clinical trial with our CAR. The development of an effective CAR-T treatment for patients with r/r T-ALL would be a major advance in a neglected clinical area.


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Description Anti-CCR9 CAR-T for children with relapsed/ refractory T cell acute lympphoblastic leukaemia (CI Sara Ghorashian)
Amount £2,800,000 (GBP)
Organisation Great Ormond Street Hospital Children's Charity (GOSHCC) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2024 
End 05/2028
Description Blood Cancer UK Grant reference: 23029 Project grant: Immunocompetent CRISPR Activation Screening To Identify Transcription Factors To Prolong CAR-T Persistence In Multiple Myeloma
Amount £322,447 (GBP)
Organisation Blood Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2023 
End 12/2026
Description Combinatorial Targeting of T-ALL with Chimeric Antigen Receptor (CAR) T Cell Therapy
Amount £280,000 (GBP)
Organisation Blood Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2023 
End 04/2026
Description Immunocompetent in vivo CRISPR screening to identify key transcription factors which enhance persistence and efficacy of CAR-T cells in cancer
Amount £458,657 (GBP)
Funding ID MR/Y001184/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2023 
End 10/2026
Description CAR-T interview 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Interview for UCL podcast
Year(s) Of Engagement Activity 2024
Description Interview and publicity for BCUK 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact BCUK Christmas appeal
Year(s) Of Engagement Activity 2023
Description UCL CAR-T PPI group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Established a PPI focus group to review preclincial CAR-T research
Year(s) Of Engagement Activity 2023