CD21 directed CAR-T cell immunotherapy for relapsed/refractory T-cell acute lymphoblastic leukaemia (T-ALL)

T-cells are cells of our immune system that look for and destroy infected cells. Since cancer cells arise from our own tissues, T-cells do not usually recognize and attack them. Medical science has long sought to find a way to bring our immune system into the fight against cancer. Recently, a technology called "CAR T-cell therapy" has achieved this - T-cells are taken from a patient's blood, "re-programmed" to recognize cancer by genetic engineering and infused back.

CAR T-cell therapy has been extremely successful in treating children with a type of leukaemia called B-Acute Lymphoblastic leukaemia (B-ALL) who have failed to respond to chemotherapy. In studies in the US, CAR T-cell therapy has resulted in almost 100% response, with about 60% of patients staying in remission. At UCL, we have a study called CARPALL open at GOSH, which is showing similar results.

About 15% of children and 25% of adults with ALL have T-ALL rather than B-ALL. Although these leukaemias are related, T-ALL cells have different proteins on their surface and this means current CAR therapy cannot be used. T-ALL is a relatively rare disease and there are no new treatments on the horizon - patients who have failed standard therapy have a poor prognosis despite very intensive chemotherapy and bone-marrow transplants.

We have found a target protein on T-ALL cancer cells against which we propose to develop a CAR therapy so that children and adults with T-ALL who have failed standard treatment can receive CAR T-cells. Since B-ALL and T-ALL are related, we believe there is a good chance that this CAR therapy will work in T-ALL. Given our experience - nine open CAR studies at UCL, we are confident this funding will lead to a phase I study.

Chimeric Antigen Receptors (CARs) are synthetic signalling molecules used to redirect T-cells to kill tumours expressing a target antigen. CAR T-cells against CD19 are transforming the treatment of children with relapsed/refractory B-ALL. In recent clinical studies of paediatric B-ALL, remission rates close to 100% have been reported, with ~60% of patients achieving sustained responses.

However, some 15% of paediatric and 20-25% of adult ALL cases are of T-lineage (T-ALL) and are therefore not suitable for treatment with anti-CD19 therapy. T-ALL remains a challenging clinical problem with an approximately 20% relapse rate. It is a devastating disease for those who fail standard intensive chemotherapy with only approximately 20% achieving remission with salvage chemotherapy resulting in extremely poor long-term survival rates for those cases. With the intensity of both frontline and relapse therapies, treatment-related mortality is a significant cause of treatment failure. Therefore, further intensification of chemotherapy is not an option resulting in the need for targeted therapies with minimal toxicity. No novel therapies have been successfully developed for T-ALL in recent years so there is a high unmet need for new treatments.

Given the success of anti-CD19 CARs in B-ALL, development of comparable strategies for T-ALL is highly desirable. However, this is challenging for multiple reasons. Targeting CD19, a pan B-cell antigen, results in B-cell aplasia which an be alleviated by infusion of pooled immunoglobulins. In contrast, targeting a pan-T-cell antigen results in unacceptable immunosuppression which cannot be mitigated, requiring subsequent salvage bone marrow transplantation. A T-ALL surface antigen with expression largely confined to the malignant T-ALL compartment, with acceptable off-tumour expression has long been sought. We believe we have identified such an antigen and would like to develop this further.

The most important beneficiaries of this research we hope will be adults and children with T-ALL. The ultimate aim of the research is a phase I/II clinical trial of CAR-T cell therapy in relapsed/refractory T-ALL. No such clinical trial currently exists in the UK so this would give these patients access to a novel targeted therapy that is currently unavailable to them. We hope that if successful (as this therapy has been in B-ALL) this could revolutionize the long term survival prospects of these patients. This would have potential impacts long-term on public health and health economics. The treatment of children and adults with T-ALL is of high intensity, lasting many years, frequently resulting in prolonged patient hospital admissions and intensive care. This research will enhance the
capacity to provide targeted therapies to those that will benefit most from them and potentially allow de-escalation of therapies and their incumbent toxicities and cost for others.

There will naturally be an academic benefit - both to researchers working internationally in the field of CAR-T cell therapeutics but also in cancer researchers seeking to understand more about the biology of T-ALL. This is a novel approach to developing CAR-T cell therapies for T-ALL compared to that done to date and so will be of considerable interest to those researchers.

This project lies at the interface between basic clinical science and translational medicine. A research assistant employed on this grant would have the opportunity to explore and develop understanding and techniques in basic T-ALL biology, right through to generation and pre-clinical testing of a CD21 CAR. This would give a research assistant considerable laboratory exposure and training in a wide range of laboratory techniques which would be of benefit to them personally. We hope this project would be inspirational and encourage a future career in research. This would be contributing to improving the research skills of the UK's workforce.

Furthermore, the majority of the leaders in the field of CAR-T cell therapies are currently from the United States. If successful, this project would increase the scientific reputation of one of the UK's leading academic institutions and the UK's international academic standing in the field of immunotherapeutics.
Finally, if successfully translated into a clinical trial this would be of benefit to our partner NHS organization - UCLH by improving the reputation of the NHS as pioneers in translational research.