Chakraverty Group: Haematopoietic Transplantation and Immunotherapy

MRC Molecular Haematology Unit MRC Weatherall Institute of Molecular Medicine Nuffield Division of Clinical Laboratory Sciences

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 our 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 tumour-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; surviving patients may go on to develop chronic GVHD, a pro-fibrotic maladaptive repair process 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, 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.

Our research is focussed on several areas:

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.
Identifying determinants of response in patients where adoptive T cell therapy is successful or unsuccessful in eliminating leukaemia. With Paresh Vyas (UOXF), Hans Stauus and Adele Fielding (UCL), we are using information from patient samples to propose molecular pathways involved in loss of immunity and testing their significance using in vivo models.
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.
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.

Clinical Trials

We have developed a translational research program in T cell immunotherapy with a track record of delivering proof-of-concept trials in human patients. We have led several innovations to improve the therapeutic index of transplantation including optimization of methods for T cell depletion, graft manipulation and treatment of GVHD. Professor Chakraverty is Medical Director of IMPACT, one of the first trial acceleration programs for transplantation and cellular therapy worldwide. Through IMPACT, he oversees delivery of the national portfolio of prospective intervention trials across over 20 centres in the UK.