Pre-Clinical Laboratory Research
CVI funded staff are principally employed work associated with clinical trials. However, they also carry out laboratory based, pre-clinical research on vaccine formulation and other ways to employ the immune system to destroy tumours.
Maturation of dendritic cells
The CVI is funding a project to investigate the optimal way in which to make dendritic cells more effective in stimulating immune responses. There are a great range of variable factors which must be studied in order to develop dendritic cells that would provide the most optimal vaccine.
David Find Memorial Studentship
The CVI is currently funding a three year PhD studentship, which started in October 2006. The David Fine Memorial studentship research is based on the idea that tumour cells, when treated in a way that makes them die, produce factors which activate an important immune cell; the dendritic cell. From previous research we know that tumours cells die, and make certain substances, when they are treated with two chemicals that mimic the conditions of a viral infection. We have also shown that these substances induce changes in dendritic cells that are likely to make them better at stimulating an immune response.
Using state-of-the-art technology a list of factors has been identified which are produced by dying tumour cells and which may contribute towards the activation of an immune response. Understanding these processes may result in the development of drugs that can be used to target dendritic cells in the body and improve dendritic cell vaccine design and thus help patients to generate immunity to their tumours.
Biomarkers and Immune Response in Melanoma Patients
The field of immunotherapy has lagged behind the rest of the Oncology field in discovering new biomarkers specific to vaccine treatments. Biomarkers represent a way of understanding what is happening clinically to a patient. Often these represent a test which predicts the outcome of a type of treatment or which is used diagnostically when it is difficult to see the tumour (for example PSA in prostate cancer).
Analysis of the serum from melanoma patients who had received a dendritic cell vaccine is underway to look for biomarkers unique to this treatment. Initial results suggest that it may be possible to predict which patients will benefit by applying a test prior to vaccination. This would obviously be of great advantage since it would clarify whether patients have a chance of responding to the vaccine at an early time point.
Work from Professor Dalgleish’s laboratory suggests that dendritic cell vaccination biases the subtype of antibody produced in patients who respond clinically to the vaccine. Studies have been expanded to look for potential specificity of these antibodies to answer the question; does DC vaccination lead to antibodies that recognise tumours or is this effect wholly non-specific? This might provide one other explanation for the effect of DC vaccination.
Gamma-delta cells
Gamma delta cells are a type of T cell which recognise and kill tumours. It is well known that factors produced by bacteria also stimulate these cells. Thus it may be possible to stimulate gamma-delta T cells with bacteria in the laboratory. Of particular interest is the use of those bacteria that have already been shown to have some anti-cancer effects (BCG and M vaccae). Professor Dalgleish’s work has already demonstrated that mixing these bacteria with gamma-delta cells extracted from human blood does indeed lead to stimulation of gamma-delta cells. These studies will be ongoing for some years but the preliminary data is encouraging and point towards several important possibilities; (1) that the stimulation of gamma-deltas by bacteria explains, in part, the effectiveness of BCG treatment in bladder cancer and M vaccae in lung and melanoma; (2) that we may be able to identify components of the bacteria that do this; (3) that this may lead to a method of specifically stimulating gamma-delta cells outside the body to be used as a therapy in cancer patients. These studies fit in with Professor Dalgleish’s other clinical interests which involve manipulation of gamma-delta cells for the treatment of melanoma.
CVI funded staff are principally employed in the production of vaccines for clinical trials. However, they also carry out laboratory based pre-clinical research on vaccine formulation and ways to employ the immune system to destroy tumours.
Maturation of dendritic cells
The CVI is funding a project to investigate the optimal way in which to bring dendritic cells to maturity and at which stage of this process the dendritic cells can be loaded. There are a great range of variable factors which must be studied in order to provide the most optimal vaccine. Work in this area is progressing well and two publications in this area are expected to be submitted soon to scientific journals.
David Find Memorial Studentship
The CVI is currently funding a three year PhD studentship, which started in October 2006, to investigate chemicals released by tumour cells which have been induced to die by a process called “apoptosis”. It is believed that such chemicals will have affects on the maturation of dendritic cells and that a better understanding of this process will help to improve the formulation of dendritic cell vaccines.
Biomarkers and Immune Response in Melanoma Patients
Later this year the CVI will fund a postdoctoral position to develop new strategies to utilise serum and tissue samples using samples taken from patients on clinical trials undertake studies on samples taken from Melanoma patients who are on the dendritic cell trial. It is hoped that the new scientist will develop new strategies. Clinical trials for vaccines, currently use a limited range of techniques to look at patients’ immune responses and these do not consistently predict which patients are responding clinically to the treatment. It is hoped that by using a “biomics” approach that markers can be looked for which are more predictive of a clinical response and may also help to explain the underlying biology of these responses. Such studies are important not only because they improve our understanding of patient responses but also because they may provide non-clinical ways to monitor patient responses.
M vaccae
In parallel with the clinical trial for Mycobacterium vaccae the CVI will fund projects to understand how this treatment might work. One such project is to look at how the M vaccae stimulates other immune cells such as dendritic cells and gamma-delta cells (a type of T cell). Gamma-delta cells may be of particular interest since when stimulated in culture it may be possible to reintroduce them into patients to fight off their cancer.
Studies on the Immunology of Graft Transplantation in the Treatment of Leukemia
The CVI has agreed to fund a two year study of leukaemia which will start in August 2007. The study will be undertaken as a collaboration between Professor Dalgleish’s group and Suparno Chakrabarti, Consultant in Haematology (BMT and Haematol-oncology at St George’s Hospital, London.
Leukaemic patients are given Bone Marrow Transplantation because the chemotherapy that they receive kills their own bone marrow cells; these are the cells that are used to generate cells of the immune system. There is now the suggestion that transplantation of blood cells from umbilical cord will do the same task since the cord contains stem cells similar in nature to those of the bone marrow. Usually transplantation would be done from a donor with a closely matched tissue type. Recently, grafts from two partially matched cord bloods were shown to establish well (i.e. were not rejected) and to provide a source of functioning white blood cells.
The purpose of this study is to determine the importance of NK cells (a type of white blood cell) in the cord blood graft. NKs are known to be active against tumours and research has suggested that the NKs derived from the donor cord blood may aid in the destruction of residual tumour cells. In addition they may be of importance in the engraftment process i.e. to determine whether the graft is rejected or not.
The study will look for a correlation between the presence of NK cells and aspects of the engraftment and also to look at the involvement of donor NK cells in the anti-tumour response. Similar studies have been done for bone marrow transplants but this is a unique chance to study the effects of reconstitution by cord blood stem cells.
Ultimately, if Professor Dalgleish can show the importance of NK cells, it may be possible to develop some immunotherapy to the cancer; most likely taking an "adoptive immunotherapy" approach where the NK cells are grown and activated in culture and are then reintroduced into the patient. It is hoped that this project will lead to clinical trials in humans.
