Our group is interested in developing novel immunotherapeutic approaches for leukaemia. Clinical approaches currently used include allogeneic haematopoietic stem cell transplantation, chimeric antigen receptor T cell therapy and immune checkpoint inhibitors. While each of these approaches can be successful, they also fail in many patients as a result of tumour adaptations or diminished function of immune cells. Enhanced immunity can also lead to immune-related adverse events due to on- or off-target effects. We are exploring the mechanisms that underpin these failures and using this information to devise new strategies that can be translated into early phase clinical trials.
About the research
Graft-versus-leukaemia (GVL), a process by which graft T cells ‘reject’ leukaemia after transplantation, is the prototypic model for T cell therapy; studying the mechanisms that underpin its success or failure have broad relevance to other T cell-mediated anti-tumour immune responses. In silico pipelines for discovery of tumor-expressed antigens and novel therapies that target immune evasion mechanisms (small molecule, biological, immune cell transfer) are potential strategies to sustain or reimpose GVL.
Graft-versus-host disease (GVHD) is an important immune-related adverse event initiated by donor immune cells following allogeneic haematopoietic stem cell transplantation. GVHD targets epithelial stem cells at barrier surfaces, while simultaneously blocking mechanisms essential for regeneration and repair; surviving patients may go on to develop chronic GVHD, a pro-fibrotic state with limited therapeutic options. A major unresolved question is why GVHD resolves in some patients, whereas in others it rapidly overwhelms the capacity for epithelial regeneration/ repair, or transitions to a maladaptive fibrotic state. To answer this question, we are using information from patient samples and interrogating potential mechanisms of tissue injury in clinically relevant models of transplantation.
Potential areas of research for new PhD students:
1. Discovery of cellular and molecular elements within the bone marrow microenvironment that regulate persistence and functions of anti-leukaemia chimeric antigen receptor T cells. In collaboration with Cristina lo Celso (Francis Crick), we are using a combination of genetic and in vivo imaging approaches to identify critical T cell-stromal interactions and decipher how they are affected by leukaemia or its treatment.
2. Identifying determinants of response in patients where adoptive T cell therapy is successful or unsuccessful in eliminating leukaemia. With Paresh Vyas, we are using information from patient samples to propose molecular pathways involved in loss of immunity and testing their significance using in vivo models.
3. An analysis of ‘hidden’ GVHD where injury to the stroma of lymphoid organs disables immune tolerance mechanisms that normally prevent autoimmunity. With Ivan Maillard, University of Pennsylvania, we are developing new tools to track developmental trajectories of stromal cells in adult lymphoid organs and evaluating their response to injury.
4. Determine mechanisms of treatment resistance in GVHD. By using in vivo models that allow combined interrogation of gene transcription and lineage history, we are are seeking to identify the mechanisms by which T cell resistance to glucocorticoids emerges; this information could be used to identify GVHD patients at risk of treatment failure much earlier and to devise novel targeted approaches to resolve inflammation.
PhD students will develop new skills in cell culture, high parameter flow cytometry and single cell sequencing, CRISPR gene editing and models that incorporate in vivo imaging. Students will aslo have opportunities to join the laboratories of our collaborators for specific projects. Professsor Chakraverty is also an attending physician in the transplant amd immunotherapy program in Oxford; accordingly, there will be a strong emphasis on focussing our research questions in areas that have translational relevance. Access to clinical samples has the potential to increase research impact and to generate new hypotheses that can be tested in the laboratory. Recent prizes won by PhD students include Best Abstract at British Society of Haematology Meeting 2012 (Dr. Ben Uttehnal), Best Abstract at British Society of Gene Therapy 2012 (Dr. Sara Ghorashian), Best Abstracts at British Society of Bone Marrow Transplantation in 2013 (Dr. Ben Carpenter) and 2014 (Dr. Santos e Sousa), Best Science Award for Physicians, European Society for Blood & Bone Marrow Transplantation 2016 (Dr. Santos e Sousa), and Academy of Medical Science Lord Leonard and Lady Estelle Wolfson Prize 2017 (Dr. Anjum Khan).
Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.
The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.
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