Theme 1: Precision T cell therapies

Current landscape

Right now, doctors treat blood cancers such as acute myeloid leukaemia (AML) using radiation and chemotherapy, followed by allogeneic haematopoietic cell transplantation (allo-HCT), where healthy blood-forming cells from a donor replace a patient's own stem cells.

After the transplant, some of the donor-derived T cells (a type of white blood cell) target and kill blood cancer cells in the patients, referred to as the 'graft versus leukaemia' or GvL effect. However only a minority of patients survive without either relapse of the blood cancer or development of severe graft-versus-host disease (GvHD), because donor-derived T cells can also end up targeting and damaging healthy cells in the patient.

Theme aims

Work in Theme 1 aims to develop T cell therapies that target leukaemia cells without causing GvHD and maintain strong anti-leukaemia activity over time to reduce the risk of relapse.

Our expertise and team

Teams led by Professors Ronjon Chakraverty, Persephone Borrow and Paresh Vyas have found a way to identify T cell receptors (TCRs) that react to blood cancer cells. TCRs bind to particular proteins that can be found on the surface of blood cancer cells. This prompts the T cell to react and kill the cancer cell.  If we can make T cells that express these cancer-specific TCRs, then the cells could be used as a treatment for several different kinds of blood cancer. These treatments would not need to be manufactured to match the cells of each individual patient; they would work for lots of different people, known as an ‘off-the-shelf’ therapy. In partnership with Oxford Biomedica, we are designing a way to test how T cells might express cancer-specific TCRs.  We hope that this work will lead to clinical trials to test these TCRs in patients for the first time.

 OUR RESEARCH APPROACH

TCRs bind to cell surface-displayed protein fragments that are not usually present on the surface of healthy cells and enable them to detect and attack abnormal cells such as cancer cells or cells infected with viruses. As there are many genetic differences between one person and another, some of the donor-derived T cells in patients who have received a transplant for leukaemia may attack healthy patient cells because they are slightly different to the donor's healthy cells and cause GvHD.  We are therefore identifying T cell receptors that target T cells to kill leukaemic cells but not damage healthy tissues. 

We have developed a method for screening donor-derived T cells present in AML patients who were successfully treated by allo-HCT and did not develop severe GvHD to identify T cells reactive with cell-surface-displayed fragments of proteins that are genetically different in the patient and donor. In a pilot study we used this approach to isolate donor-derived T cells recognising several different targets on patient AML cells, providing an initial set of TCRs that we can test for their ability to direct T cells to combat AML cells but not healthy cells. We are also refining our screening pipeline to focus on identification of T cells reactive with targets that are selectively expressed on AML cells in a high proportion of different patients, and plan to employ complementary approaches to identify T cell receptors with ideal therapeutic properties.

We are also exploring how best to isolate and expand T cells that will be modified to express therapeutic TCRs. In early clinical studies of T cell therapies, it is increasingly clear that both the type of T cell infused and its persistence in the patient after infusion are critical for success. We are therefore investigating whether there are particular types of T cells that will be better suited for this purpose when given alone or in combination. In additional work, we will test whether tweaking how a T cell reacts following infusion can improve the safety of the treatment.