Characterisation of Positive and Negative Influences in Tumour Immunity

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

The main function of our white cells is to eliminate infectious agents such as bacteria and viruses. These cells form part of the immune system and their activation is known as an immune response. Certain types of white cells, known as regulatory T cells, are believed to dampen down immune responses that are considered harmful ?these may be immune responses directed towards normal, uninfected tissues. Since tumours arise from normal tissues, it was considered possible that these regulatory T cells inhibit immune responses to tumours. Several laboratories have shown that the cells do indeed inhibit immune responses to tumours, responses that could otherwise promote tumour destruction.
A two-pronged approach is now warranted to find out how this information can be harnessed for the purposes of treating people with cancer. Firstly, the immune responses capable of promoting tumour destruction must be identified and secondly the precise way in which regulatory T cells act to stop these responses working effectively must be discovered. This approach will allow us to determine how the immune system can be manipulated for the treatment of a wide variety of cancers, including breast cancer, lung cancer, ovarian cancer and colorectal cancer.

Technical Summary

Many fundamental questions remain unanswered in the field of tumour immunology. The type of immune effector cells / molecules capable of controlling tumour growth in vivo have not yet been definitively identified. In addition, whilst many pathways of tumour-induced immunosuppression are thought to contribute to the overall paucity of anti-tumour immunity, these pathways remain poorly characterised. A resurgence of interest in T cell mediated tolerance has revealed that a subpopulation of T cells, named regulatory T cells (Tregs) may play a key role in inhibiting effective anti-tumour immunity. These Tregs, identified by expression of the CD4 antigen and the forkhead transcription factor, Foxp3, keep innate and adaptive immune responses in check; suppress responses to self- and non-self antigens and impinge on almost all aspects of immune activity including transplantation, allergy, infection, autoimmunity and tumour immunity. A clear objective of Treg research is to determine how they can be manipulated therapeutically to treat a wide range of immune-based diseases.
Cancer is a disease where manipulation of Treg activity has obvious therapeutic potential. An enormous body of work indicates that overall, Tregs are present at an increased frequency in the peripheral blood lymphocytes (PBL) of patients with cancer compared to healthy controls. Depletion of Tregs from PBL in vitro, uncovers T cell responses to tumour antigens and, in vivo, depletion of Tregs can enhance immune responses generated following vaccination. Furthermore, several reports indicate that high frequencies of Tregs correlate with more advanced disease implying that Tregs facilitate progression of cancer. I hypothesize that tumour development can be prevented or controlled at an early stage by effective immune responses. However, these responses are suppressed by Tregs. The identification of immune mechanisms of tumour control and an understanding of how Tregs impinge on these will enable therapeutic strategies to be developed for the successful treatment of patients with cancer. Detailed investigations into both issues will be undertaken. Specifically, the study aims to identify the effector cells/molecules that participate in controlling tumour growth in vivo and to assess the consequences of this immune activity on the fate of the tumour. In addition, an investigation of Treg activity in tumours will be performed. The overall aim of this two-pronged approach, which involves evaluating both positive and negative influences on tumour immunity, is to inform the design of more effective therapeutic immune interventions for patients with cancer.
 
Description PhD Studentship
Amount £80,000 (GBP)
Organisation Cancer Research Wales 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description PhD Studentship
Amount £84,300 (GBP)
Organisation Cancer Research Wales 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description PhD Studentship
Amount £80,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description PhD Studentship
Amount £80,000 (GBP)
Organisation GW4 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 12/2019
 
Description Programme Grant
Amount £800,000 (GBP)
Organisation Cancer Research Wales 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 08/2021
 
Description Project Grant
Amount £313,321 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Analysis of clonal expansion in tumours 
Organisation Cardiff University
Department Infection and Immunity
Country United Kingdom 
Sector Academic/University 
PI Contribution Generated model whereby tumour-infiltrating T cells can be isolated and characterised.
Collaborator Contribution Sorting highly purified T cell populations, use of 18-colour flow cytometry, RACE-PCR for T cell receptor analyses
Impact Paper in Cancer Research
Start Year 2009
 
Description Induction of HEV in tumours 
Organisation Cardiff University
Department Infection and Immunity
Country United Kingdom 
Sector Academic/University 
PI Contribution Identified that regulatory T cells inhibit generation of HEV
Collaborator Contribution Ann Ager is an expert in T cell trafficking thus her expertise has been pivotal to driving our research forward
Impact T-cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T-cell depletion. Hindley JP, Jones E, Smart K, Bridgeman H, Lauder SN, Ondondo B, Cutting S, Ladell K, Wynn KK, Withers D, Price DA, Ager A, Godkin AJ, Gallimore AM. Cancer Res. 2012 Nov 1;72(21):5473-82. Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics. Ondondo B, Jones E, Hindley J, Cutting S, Smart K, Bridgeman H, Matthews KK, Ladell K, Price DA, Jackson DG, Godkin A, Ager A, Gallimore A. Int J Cancer. 2014 May 1;134(9):2156-67.
Start Year 2011
 
Description Induction of HEV in tumours 
Organisation Upstate Medical University
Country United States 
Sector Academic/University 
PI Contribution Identified that regulatory T cells inhibit generation of HEV
Collaborator Contribution Ann Ager is an expert in T cell trafficking thus her expertise has been pivotal to driving our research forward
Impact T-cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T-cell depletion. Hindley JP, Jones E, Smart K, Bridgeman H, Lauder SN, Ondondo B, Cutting S, Ladell K, Wynn KK, Withers D, Price DA, Ager A, Godkin AJ, Gallimore AM. Cancer Res. 2012 Nov 1;72(21):5473-82. Progression of carcinogen-induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics. Ondondo B, Jones E, Hindley J, Cutting S, Smart K, Bridgeman H, Matthews KK, Ladell K, Price DA, Jackson DG, Godkin A, Ager A, Gallimore A. Int J Cancer. 2014 May 1;134(9):2156-67.
Start Year 2011
 
Description T cell receptor analysis 
Organisation Imperial College London
Department Division of Immunology and Inflammation
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated a tumour model whereby the relationship between regulatory and conventional T cells can be characterised.
Collaborator Contribution Established methods for analysis of T cell receptor repertoires
Impact Publication in Cancer Research
Start Year 2008
 
Title CLINICAL TRIAL - TACTICC 
Description The intervention was a pilot study to assess the effect of regulatory T cell depletion on 5T4-containing MVA (TROVAX®) vaccination in patients with inoperable metastatic colorectal cancer. In this randomised, open-label, phase 2 clinical trial, TaCTiCC (TroVax® and Cyclophosphamide Treatment in Colorectal Cancer), we recruited patients with inoperable, metastatic CRC, with prior stable or responding disease following 12 weeks standard chemotherapy. Patients were centrally randomised to receive either no treatment (watch & wait unless clinically indicated; Group 1), metronomic oral 50mg B.D. CPM on treatment weeks 1 & 3 (Group 2), intramuscular injections of 1x109 TCID50 TroVax® on treatment weeks 4, 6, 8, 10, 12 and 16 (Group 3), or a combination of the two treatments (Group 4). The primary endpoint was the magnitude of anti-5T4 immune responses generated at treatment week 7, as determined by the presence of 5T4-specific T cell responses by IFN-? ELISPOT and 5T4 antibodies by ELISA. Secondary endpoints included analysing the kinetics of anti-5T4 responses, progression-free survival (PFS) and overall survival (OS). This trial is registered with EudraCT (2010-024380-41) and the ISRCTN registry 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Initial development
Year Development Stage Completed 2016
Development Status Actively seeking support
Clinical Trial? Yes
Impact Prior depletion of Tregs by CPM does not boost immune responses generated to TroVax® vaccination, however, both CPM and TroVax® independently induced beneficial anti-tumour immune responses resulting in prolonged survival of end-stage CRC patients without toxicity. These data warrant further investigation of the two treatments in separate, larger clinical trials.Funding applications are underway. 
URL http://www.isrctn.com/ISRCTN54669986
 
Description Animal Workers: Cardiff University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact 10 animal workers attended the talk and asked questions regarding the research both in relation in animal health and welfare and the science and its implications for advances in medicine

The audience were very pleased to improve their understanding of work in which they participate directly.
Year(s) Of Engagement Activity 2011
 
Description Newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Results of the activity cannot yet be established.

It is too soon to determine whether there are any notable impacts.
Year(s) Of Engagement Activity 2012