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Gene correlation network showing differences in gene expression of effector T cells derived from the bone marrow or peripheral tissues affected by GVHD.


Weatherall Institute of Molecular Medicine

Oxford United Kingdom Molecular Biology Medicine

About the Project

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).

More information about training opportunities can be found on our website.

Funding Notes

Funding for this project is available to scientists through the WIMM Prize Studentship and the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2021 entry, the application deadline is 8th January 2021 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.


References

1. Dertschnig S., Evans P., Santos e Sousa P., Manzo T., Ferrer I.R., Stauss H.J., Clare Bennett C. and Chakraverty R. 2020. Graft-versus-host disease reduces lymph node expression of tissue-restricted antigens and promotes autoimmunity. Journal of Clinical Investigation 130:1896-1911

2. Ferrer IR, West HC, Henderson S, Ushakov DS, Santos E Sousa P, Strid J, Chakraverty R, Yates AJ, Bennett CL. 2019. A wave of monocytes is recruited to replenish the long-term Langerhans network after immune injury. Science Immunology 2019 4(38); pii: eaax8704

3. Khan AB, Carpenter B, Sousa PSE, Pospori C, Khorshed R, Griffin J, Velica P, Zech M, Ghorashian S, Forrest C, Thomas S., Gonzalez Anton S., Ahmadi M., Holler A’, Flutter B., Ramirez-Ortiz Z., Means T.K., Bennett C.L., Stauss H., Morris E., Lo Celso C., Chakraverty R. 2018. Redirection to the bone marrow improves T cell persistence and antitumor functions. Journal of Clinical Investigation 128:2010-2024

4. Santos ESP, Cire S., Conlan T., Jardine L., Tkacz C., Ferrer I.R., Lomas C., Ward S., West H., Dertschnig S., Blobner S., Means T.K., Henderson S., Kaplan D.H., Collin M., Plagnol V., Bennett C.L. and Chakraverty R. 2018. Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease. Journal of Clinical Investigation Insight 3(5) pii 90711

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