Characterisation and repair of T cell defects in leukaemia and lymphoma
Lead Research Organisation:
CANCER RESEARCH UK
Department Name: UNLISTED
Abstract
The hypothesis at the root of this study is that a healthy immune system will recognise a cell when it becomes malignant and destroy it thus preventing the growth and spread of cancer. Therefore cancer can only occur when this process goes wrong. If we could find out how the immune system interacts with cancer cells and what abnormalities are occurring in this interaction we may then be able to develop strategies to improve the immune response to cancer. This would represent a potentially novel form of treatment and would be expected to improve the response to vaccination therapies that are already undergoing clinical trials in some cancers.
This study will look at T cell function in blood samples from patients with leukaemia and lymphoma and then go on to look at mechanisms of improving that function in a mouse model. Finally, attempts will be made to generate a patient tumour-specific T cell response in vitro using the information gained in the earlier parts of the study. This research will be carried out by a clinical research fellow in the Institute of Cancer, Charterhouse Square, London.
This study will look at T cell function in blood samples from patients with leukaemia and lymphoma and then go on to look at mechanisms of improving that function in a mouse model. Finally, attempts will be made to generate a patient tumour-specific T cell response in vitro using the information gained in the earlier parts of the study. This research will be carried out by a clinical research fellow in the Institute of Cancer, Charterhouse Square, London.
Technical Summary
The aims of the study are to explore the impact of cancer on the host immune system and to subsequently develop strategies to boost T cell immune responses against cancer. The objectives are firstly to examine T cell function in a range of haematological malignancies, building on and extending work already published in chronic lymphocytic leukaemia (CLL). Secondly, to use a mouse model of CLL to examine ways in which the T cell defects already documented in CLL can be repaired. Thirdly, to investigate further the nature of tumour-specific allogeneic T cells demonstrated post transplantation and finally to use the knowledge gained in the preceding parts of the study to overcome the barriers to generation of an autologous T cell response to malignancy.
In order to achieve these objectives, advantage will be taken of the large bank of stored peripheral blood and bone marrow samples available in the department. Cell isolation technology will be used to separate T cells from samples from patients with AML, ALL and lymphoma. The gene expression profile of these cells will then be analysed. Functional studies will also be performed. These will include characterising T cell surface antigen expression by flow cytometric analysis and examining T cell proliferative and effector function. Methods to repair the T cell defects seen in CLL will be examined in a mouse model already available in the department. The impact on T cell function of various immunotherapeutic interventions e.g. cytokines, anti-CD3 and anti-CD28 monoclonal antibodies and immunomodulatory drugs will be assessed by gene expression profiling as well as ex vivo analysis of T cell function. This work will then be extrapolated to humans by firstly examining the phenotype of tumour-specific donor T cells demonstrated in patients post allogeneic transplant. Ex vivo human cell culture work will then build on the knowledge gained from the earlier parts of the study in order to attempt to generate autologous tumour-specific T cells that can effectively kill cancer cells.
This study aims to provide insight into the interaction between cancer and the host immune system both by documenting induced abnormalities in immune function and then by investigating methods by which those abnormalities can be reversed. Repairing patient T cell defects is a major step towards initiating an effective immune response to cancer and, when combined with effective antigen presentation in the form of vaccine therapy, may have major implications for cancer treatment.
In order to achieve these objectives, advantage will be taken of the large bank of stored peripheral blood and bone marrow samples available in the department. Cell isolation technology will be used to separate T cells from samples from patients with AML, ALL and lymphoma. The gene expression profile of these cells will then be analysed. Functional studies will also be performed. These will include characterising T cell surface antigen expression by flow cytometric analysis and examining T cell proliferative and effector function. Methods to repair the T cell defects seen in CLL will be examined in a mouse model already available in the department. The impact on T cell function of various immunotherapeutic interventions e.g. cytokines, anti-CD3 and anti-CD28 monoclonal antibodies and immunomodulatory drugs will be assessed by gene expression profiling as well as ex vivo analysis of T cell function. This work will then be extrapolated to humans by firstly examining the phenotype of tumour-specific donor T cells demonstrated in patients post allogeneic transplant. Ex vivo human cell culture work will then build on the knowledge gained from the earlier parts of the study in order to attempt to generate autologous tumour-specific T cells that can effectively kill cancer cells.
This study aims to provide insight into the interaction between cancer and the host immune system both by documenting induced abnormalities in immune function and then by investigating methods by which those abnormalities can be reversed. Repairing patient T cell defects is a major step towards initiating an effective immune response to cancer and, when combined with effective antigen presentation in the form of vaccine therapy, may have major implications for cancer treatment.