Prof Ronjon Chakraverty

Research projects
Ronjon Chakraverty

Prof Ronjon Chakraverty

Professor of Haematology and Cellular Immunotherapy

Prof. Ronjon Chakraverty

Contact

Professor Ronjon Chakraverty
Institute of Immunity and Transplantation and Cancer Institute
Royal Free Hospital
Rowland Hill Street
London NW3 2PF
UK
r.chakraverty [at] ucl.ac.uk
T. +44 (0)20 7794 0500  Ext. 33482

Research area

Graft-versus-host-disease, Graft-versus-leukaemia, T cell immunotherapy

Research summary

Our group is interested in understanding the biology of immune responses following allogeneic haematopoietic stem cell transplantation (allo-HSCT).  Graft-versus-host disease (GVHD) is a major clinical problem and is caused by donor T cells within the graft that recognize antigens found in the patient but not the donor. Following allo-HSCT, activated donor T cells are recruited to peripheral organs where they cause severe injury, for example colitis or dermatitis.  A similar immune reaction can occur in the lymphoid organs and bone marrow, a process co-opted therapeutically to achieve a graft-versus-leukaemia (GVL) effect.  Although GVL can be separated from GVHD in experimental models, few of the identified strategies have been successfully translated into clinical practice.  This failure reflects considerable redundancy in the mechanisms leading to GVHD and a lack of whole system approaches that readily address the complexity of this disorder.  

Together with Dr. Clare Bennett, we have developed clinically relevant pre-clinical models of allo-HSCT permitting us to track evolving immune responses in considerable detail and at multiple sites.  We are working with computational biologists (Dr. Vincent Plagnol, Institute of Genetics) to develop a systems approach for identifying the cellular and molecular mechanisms that dictate the development of GVHD versus GVL.  In particular, we are interested in how the mode of antigen presentation by different cells and tissues influences the type of immunity that is elicited.  In collaboration with Prof. Hans Stauss, we are also using genetic engineering to modify the behaviour of anti-tumour T cells in vivo to subvert tolerance mechanisms that lead to relapse of cancers after initial control.

Patient involvement

I am attending physician on the Bone Marrow Transplantation programme that runs at the Royal Free London and University College London Hospital, where I have a particular clinical interest in adoptive T cell therapy to prevent or treat relapse of leukaemia or lymphoma following allo-HSCT.

I am Chief Investigator of the national ProT4 Study that is testing the potential of transferring prophylactic allo-depleted donor lymphocytes following allo-HSCT.

Group members

Cara Lomas (with C. Bennett)
Severine Cire (with C. Bennett)
Simone Dertschnig
Pedro Santos e Sousa
Claire Winship
Anjum Kahn
Pamela Evans
Sophie Ward (with C. Bennett)

Recent publications

Goold H.D., Escors D., Kissenpfennig A., Malissen B., Chakraverty R. and Bennett C.L. Conventional DC are required for the activation of helper-dependent CD8 T cell responses to a model antigen after cutaneous vaccination with lentiviral vectors. Journal of Immunology 2011, 186: 4565-72.

Pospori C., Xue S., Holler A., Voisine C., Perro M., King K, Fallah-Arani F., Flutter B., Chakraverty R., Stauss H. and Morris E.  Specificity for the tumor-associated self-antigen WT1 drives the development of fully functional memory T cells in the absence of vaccination. Blood 2011 117: 6813

Bennett C.L. , Fallah-Arani F., Conlan T., Trouillet C., Goold H., Chorro L., Flutter B., Means T.K., Geissmann F. and Chakraverty R.  Langerhans Cells Regulate Cutaneous Injury by Licensing CD8 Effector Cells Recruited to the Skin. Blood 2011 117:7063-9

Soulier A., Blois S. M., Sivakumaran S., Fallah-Arani F., Henderson S., Flutter B., Rabbitt E.H., Paul M. Stewart, Lavery G.G., Bennett C., Curnow S.J. and Chakraverty R. Cell-intrinsic regulation of murine dendritic cell function and survival by pre-receptor amplification of glucocorticoid. Blood 2013 122: 3288-97

Philip B, Kokalaki E, Mekkaoui L, Thomas S, Straathof K, Flutter B, Marin V, Marafioti T, Chakraverty R, Linch D, Quezada SA, Peggs KS, Pule M.  A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood. 2014 124:1277-87

Buchan S., Manzo T., Flutter B., Rogel A., Edwards N., Zhang L., Sivakumaran S., Ghorashian S., Carpenter B., Bennett C., Freeman G.J., Sykes M., Croft M., Al-Shamkhani A. and Chakraverty R. OX40- and CD27-mediated co-stimulation synergize with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence. Journal of Immunology 2014 (in press)

Older publications

Clark F., Gregg R., Dunnion D., Piper K., Griffiths M., Mahendra P., Craddock C., Moss P.A.H., Chakraverty R. Chronic graft versus host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T-cells. Blood 2004, 103:2410-6

Freeman L., Hewison M., Hughes S., Evans K., Hardie D., Means T. and Chakraverty R. Expression of 11beta-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells. Blood 2005 106:2042-9

Cobbold M., Khan N., Tauro S., McDonald D., Osman H., Assenmacher M., Crawley C., Olavarria E., Goldman J., Chakraverty R., Mahendra P., Craddock C. and Moss P. Direct transfer of donor cytomegalovirus-specific CTL following selection by HLA-peptide tetramers. Journal of Experimental Medicine 2005 202: 379-86

Chakraverty R., Eom H., Sachs J., Buchli J., Cotter P., Hsu R., Zhao G. and Sykes M. Host MHC Class II+ antigen-presenting cells and CD4 cells are required for CD8-dependent graft-versus-leukemia responses following delayed donor leukocyte infusions. Blood 2006 108:2106-2113

Chakraverty R., Côté D., Buchli J., Cotter P., Hsu R., Zhao G., Sachs T., Pitsillides C.M., Bronson R., Means T., Lin C. and Sykes M. An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. Journal of Experimental Medicine 2006 2003: 2021-2031.

Bloor A., Thomson K., Chowdury N, Verfeuth S., Ings S., Chakraverty R., Goldstone A., Linch D., Peggs K., Mackinnon S. High response rate to donor lymphocyte infusions (DLI) following allogeneic stem cell transplantation for indolent non-Hodgkin's Lymphoma. Biology of Blood and Marrow Transplantation 2008 14:51-8

Chakraverty R, Flutter B, Fallah-Arani F, Eom HS, Means T, Andreola G, Schwarte S, Buchli J, Cotter P, Zhao G, Sykes M. The host environment regulates the function of CD8+ graft-versus-host-reactive effector cells. Journal of Immunology 2008 181:6820-8.

Thomson K., Chowdury N, Verfeuth S., Ings S., Chakraverty R., Goldstone A., Linch D., Peggs K., Mackinnon S. 2009 Reduced intensity transplantation for diffuse large B-cell lymphoma and transformed follicular lymphoma. Journal Of Clinical Oncology 2009 27; 426-32

Orti, G., Lowdell M., Fielding A., Samuel E., Pang K., Kottaridis P., Morris E., Thomson K., Peggs K., Mackinnon S. and Chakraverty R. Phase I study of high-stringency CD8 depletion of donor leukocyte infusions after allogeneic hematopoietic stem cell transplantation. Transplantation 2009 88:1312-1318.

Carpenter, B., Haque T., Dimopoulou M., Atkinson C., Roughton M., Grace S., Denovan S., Fielding A., Kottaridis P.D., Griffiths P., Mackinnon S., Emery V., and Chakraverty R. Incidence and dynamics of epstein-barr virus reactivation after alemtuzumab-based conditioning for allogeneic hematopoietic stem-cell transplantation. Transplantation 2010 90:564-570.

Lambert, J.R., Bomanji J.B., Peggs K.S., Thomson K.J., Chakraverty R., Fielding A.K., Kottaridis P.D., Roughton M., Morris E.C., Goldstone A.H., Linch D.C., Ell P.J., and Mackinnon S. Prognostic role of PET scanning before and after reduced-intensity allogeneic stem cell transplantation for lymphoma. Blood 2010 115:2763-2768.

Mead, A.J., Thomson K.J., Morris E.C., Mohamedbhai S., Denovan S., Orti G., Fielding A.K., Kottaridis P.D., Hough R., Chakraverty R., Linch D.C., Mackinnon S. and Peggs K.S. HLA-mismatched unrelated donors are a viable alternate graft source for allogeneic transplantation following alemtuzumab-based reduced-intensity conditioning. Blood 2010 115:5147-5153.

Thomson, K.J., Morris E.C., Milligan D., Parker A.N., Hunter A.E., Cook G., Bloor A.J., Clark F., Kazmi M., Linch D.C., Chakraverty R., Peggs K.S. and Mackinnon S. T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma. J Clin Oncol 2010 28:3695-3700.

Chakraverty, R., Orti G., Roughton M., Shen J., Fielding A., Kottaridis P., Milligan D., Collin M., Crawley C., Johnson P., Clark A., Parker A., Bloor A., Pettengell R., Snowden J., Pettitt A., Clark R., Hale G., Peggs K., Thomson K., Morris E. and Mackinnon S. Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD and immune reconstitution. Blood 2010, 116:3080-8

B. Flutter, N. Edwards, F. Fallah-Arani, S. Henderson, J-G Chai, S. Sivakumaran, S. Ghorashian, C. L. Bennett, G. J. Freeman, M. Sykes and R. Chakraverty. Non-hematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation. Journal of Clinical Investigation 2010, 120:3855-68

Peggs K., Kayani I., Edwards N., Kottaridis P., Goldstone A., Linch D., Hough R., Morris E., Fielding A., Chakraverty R., Thomson K. and Mackinnon S. Donor-lymphocyte infusions modulate relapse risk in mixed chimeras and induce durable salvage in relapsed patients following T cell-depleted allogeneic transplantation for Hodgkin Lymphoma. J Clin Oncol 2011, 29:971-8.

Peggs KS, Thomson K, Samuel E, Dyer G, Armoogum J, Chakraverty R, Pang K, Mackinnon S, Lowdell MW. Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation. Clin Infect Dis. 2011, 52:49-57.

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