Harnessing immune cell therapy in cancer

Allogenic stem cell transplantation (allo-SCT) is one of the most common, curative forms of cancer immunotherapy. It has been a treatment option for patients with blood cancers (including leukaemia, lymphoma and myeloma) for over 60 years.

In this type of transplant, a patient receives blood stem and immune cells from another healthy person (a donor). Although the initial aim of allo-SCT was to replenish the blood cell producing capacity that patients lose during harsh chemo- and radio-therapy treatment regimes, clinicians and researchers soon realised that donor immune cells specifically destroy the remaining cancer cells through an effect called “graft-vs-tumour”.

This remarkable curative treatment option is a standard treatment, which is routinely used in younger patients with otherwise incurable blood cancers. However, the treatment is associated with significant side effects and can result in 5-25% mortality within the first 100 days of receiving treatment. This toxicity limits wider use of the treatment.

Work currently being done by Prof Paresh Vyas and his team aims to understand the specific mechanisms and cells involved in the graft-vs-tumour effect, to develop safer, more targeted, and curative therapeutic strategies. In this way the treatment would potentially benefit more patients.

To date, we know that donor T cells, a type of immune cell, play a central role in recognition and elimination of the patient’s residual cancer cells. However, our understanding of the precise nature of these protective T cells is still incomplete. To rectify this gap in knowledge, Prof Vyas and his team are studying in depth patients who have been successfully cured with allo-SCT and why patients relapse after allo-SCT.

An important goal is to purify specific T cells that mediate the graft-vs-tumour effect. By doing this, Prof Paresh Vyas and his team aim to develop treatments that supply only the specific T cells that destroy cancer cells – i.e. develop a precision T cell therapy with potentially fewer side effects. work has wider applications beyond blood cancer.

Vyas and his team hope to take this project to a clinical trial in late 2021. This work links to Oxford-wide efforts to develop new cell therapies and appointment of Professor Ronjon Chakraverty, as Professor of Haematology with specific interest in allo-SCT, advanced cell therapies and cancer immunotherapy.

Donor T cells recognise antigens displayed on the surface of patient cells. If these antigens are expressed on acute myeloid leukaemia (AML) cells, they may lead to a therapeutic graft-versus-leukaemia (GvL) response. If antigens are also expressed on healthy patient cells, they may lead to harmful graft-versus-host disease (GvHD)

About the team

This work is led by Prof Paresh Vyas, Radcliffe Department of Medicine. His primary focus is to understand the biology of normal blood stem/progenitor cells and how changes in these cells and their environment lead to myeloid blood cancers, especially childhood and adult Acute Myeloid Leukaemia. His laboratory study the functional, genetic, epigenetic properties of heterogeneous populations of leukaemia propagating cells and cells of the microenvironment at a single cell level to understand leukaemia initiation and propagation. He also studies how AML responds to therapies.

This particular project is being performed by Dr Connor Sweeney (Wellcome Trust Clinical Research Training Fellow). It is funded by The Medical Research Council, the Wellcome Trust and the National Institutes of Health Research through the Oxford Comprehensive Biomedical Research Centre

The Vyas laboratory collaborates with multiple groups in the MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine Oxford (Nerlov, Roberts, Porcher, Milne Mead and Psaila), Professor Borrow and McMichael (T cell immunity), Majeti laboratory (Stanford) on anti-CD47 therapies, Constantinescu laboratory (Ludwig Brussels) on cytokine receptor signalling and Vassiliou (Cambridge), Jaiswal (Stanford) and Hofer (Heidelberg) laboratories on clonal haemopoiesis. He has extensive collaborations with clinical trials groups in the UK, Europe and United States.