UCL Cancer Institute

Stem Cell Transplantation and Cellular Immunotherapy Group (STIm)


Group Leader: Dr Karl S Peggs, MA MB BCh MRCP FRCPath



Our group aims to translate state-of-the art cellular therapeutics from the laboratory to the clinic for the treatment either of opportunistic pathogens or of cancer, defining the limitations of such strategies within prospective clinical studies and further interrogating the mechanisms behind success or failure within murine models. Our mission is to improve anti-cancer cellular therapeutics by critically evaluating and manipulating both the host microenvironment and characteristics of the cellular product to enhance homing and to overcome local immune regulatory checkpoints, ultimately establishing novel therapies as standard treatment paradigms in the setting of both infectious disease and malignancy.




neo-antigens pathways


Fig 1  
Fig 1 (a) Presentation of tumour-derived neo-antigens via class I and class II pathways may be enhanced by therapy with monoclonal antibodies or small molecule inhibitors, but (b) regulatory circuits likely inhibit endogenous immune responses. These immune stimulatory and immune inhibitory pathways are targets for therapeutic intervention.



Research

Stem cell transplantation is probably the most successful example of the therapeutic potential of cellular immunotherapy, delivering cures in a significant number of patients with haematological malignancies. Whilst early approaches relied heavily on the cytoreductive activity of conditioning radio-chemotherapy, more recent developments have focused on optimising the ability of the newly established donor immune system to eradicate both residual host haematopoiesis and malignant cells that have survived the conditioning phase. Attempts to prevent uncontrolled alloreactivity and immune-mediated destruction of normal healthy tissues (graft-versus-host disease), which become increasingly relevant with greater genetic disparity between donor and recipient (e.g. unrelated donor or cord blood transplants), weaken cellular immunity and increase the risk of both infection and relapse.


CTLA-4


Fig 2  
Mice genetically engineered to express the external domain of human rather than murine CTLA-4 allow dissociation of blocking activity of anti-human and anti-murine CTLA-4 antibodies.




Our group is interested in immune reconstitution and adoptive cellular therapies for viral infections following stem cell transplantation. We are also interested in the development of immunological strategies to prevent or treat disease relapse following allogeneic transplantation. These approaches include modulation of the tumour microenvironment to enhance activity and genetic modulation of effector to cells to enhance function or re-direct specificity. We are currently leading 4 UKCRN national studies evaluating both cellular therapies for cytomegalovirus infection (CMV~IMPACT, CMV~ACE/ASPECT) and allogeneic immunotherapy in Hodgkin Lymphoma (PAIReD, ReACH).



CTLA-4


Fig 3  
Isolation of effector and regulatory compartments allows reconstitution of RAG-/- mice and subsequent unicompartmental blockade.




Working in close collaboration with the Immune Regulation and Tumour Immunotherapy group (IRTI) of Dr Quezada, our group has a strong translational focus but recognises that collaborative efforts will facilitate a better understanding of the basic immunological principles governing the success or failure of immunotherapeutic interventions, and ultimately allow development of more successful clinical strategies.

The research projects being currently developed in the laboratory include:

  1. Studying how genetic modulation of CTLA-4 expression within effector and regulatory T cell populations modulates anti-tumour activity of tumour-specific T cells
  2. Studying methods to enhance homing of primed effector populations to the tumour site
  3. Studying how specific features the tumour microenvironment can predict outcomes following donor lymphocytes



Parallel translational clinical trials include:

  1. CMV~IMPACT (Immuno-Prophylactic Adoptive Cellular Therapy): a randomised phase III study of adoptive cellular therapy with CMV-specific T cells in sibling donor allogeneic haematopoietic stem cell transplants (UKCRN ID 5742)
  2. CMV~ACE/ASPECT (Alternate Donor Study of Pre-Emptive Cellular Therapy): a randomised phase IIb study of adoptive cellular therapy with CMV-specific T cells in unrelated donor allogeneic haematopoietic stem cell transplants (UKCRN ID 4816)
  3. PAIReD: Pilot of Allogeneic Immunotherapy in Refractory Disease (Hodgkin Lymphoma)(UKCRN ID 6284)
  4. ReACH: Reduced Intensity Allografting in Chemosenstive Hodgkin Lymphoma (UKCRN ID 6287)





neo-antigens pathways


Fig 4 (a)  
PET-CT images of a patient with Hodgkin Lymphoma relapsing early following allogeneic transplantation. Red lines show levels of fused PET-CT images on the right. (b) Following cytoreductive chemotherapy and donor-lymphocytes the FDG-avid lesions resolve.



 

Group Members


•  Dr Frederick Arce, LRR Postdoctoral Fellow
•  Dr Claire Roddie, MRC Clinical Fellow
•  Dr Sergio A Quezada, Group Leader Immune Regulation and Tumour Immunotherapy Group (IRTI)
•  Dr Dana Briesemeister, Postdoctoral Fellow (IRTI)
•  Jake Henry, Research Assistant (IRTI)


Collaborators


•  Dr Sergio A Quezada
•  Dr Martin Pule
•  Dr A Nathwani
•  Dr T Marafioti
•  Professor Paul Moss (University of Birmingham)
•  Cell Medica

Cell Medica logo

 



 

Selected Publications


Peggs KS, Kayani I, Edwards N, Kottaridis P, Goldstone AH, Linch DC, Hough R, Morris EC, Fielding A, Chakraverty R, Thomson KJ, Mackinnon S. Donor lymphocyte infusions modulate relapse risk in mixed chimeras and induce durable salvage in relapsed patients after T-cell-depleted allogeneic transplantation for Hodgkin's Lymphoma. J Clin Oncol. 2011 Jan 31. [Epub ahead of print]. Pubmed

Mead AJ, Thomson KJ, Morris EC, Mohamedbhai S, Denovan S, Orti G, Fielding AK, Kottaridis PD, Hough R, Chakraverty R, Linch DC, Mackinnon S, Peggs KS. HLA-mismatched unrelated donors are a viable alternate graft source for allogeneic transplantation following alemtuzumab-based reduced-intensity conditioning. Blood. 2010; 115(25):5147-53. Pubmed

Peggs, K.S.*, Quezada, S.A.*, Chambers, C.A., Korman, A.J., and Allison, J.P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009; 206:1717-1725. *contributed equally Pubmed

Peggs, K.S.*, Quezada, S.A.*, Simpson, T.R., Shen, Y., Littman, D.R., and Allison, J.P. Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J Exp Med. 2008; 205:2125-2138. *contributed equally Pubmed

Peggs KS, Segal NH, Allison JP. Targeting immunosupportive cancer therapies: accentuate the positive, eliminate the negative. Cancer Cell. 2007; 12(3):192-9. Pubmed

Peggs, K.S.*, Quezada, S.A.*, Curran, M.A., and Allison, J.P. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006; 116:1935-1945. *contributed equally Pubmed

Peggs KS, Hunter A, Chopra R, Parker A, Mahendra P, Milligan D, Craddock C, Pettengell R, Dogan A, Thomson KJ, Morris EC, Hale G, Waldmann H, Goldstone AH, Linch DC, Mackinnon S. Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet. 2005; 365(9475):1934-41. Pubmed

Peggs KS, Thomson K, Hart DP, Geary J, Morris EC, Yong K, Goldstone AH, Linch DC, Mackinnon S. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. Blood. 2004; 103(4):1548-56. Pubmed

Peggs KS, Verfuerth S, Pizzey A, Khan N, Guiver M, Moss PA, Mackinnon S. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet. 2003; 362(9393):1375-7. Pubmed