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
Abstract
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.
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.
Organisations
Publications
Horna P
(2024)
Dual T-cell constant ß chain (TRBC)1 and TRBC2 staining for the identification of T-cell neoplasms by flow cytometry.
in Blood cancer journal
Ferrari M
(2024)
Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies.
in Nature communications
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 |