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

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.

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.