Pre-Clinical Laboratory Research
CVI funded staff carry out laboratory based, pre-clinical research which aims to improve cancer immunotherapy and to better understand the ways in which the immune system can be manipulated to fight cancer.
The Effect of Chemotherapy Drugs on Immune Cells in Culture
Dr Wai Liu has been funded through the CVI since January and is investigating potential effects of chemotherapy drugs on the immune system. This is important because it has long been believed that chemotherapy is detrimental to immunotherapy and that the two should be delivered at different times.
A number of recent studies suggest that some forms of chemotherapy are able to promote immune function. Dr Liu’s results, which have just been published in the British Journal of Cancer, demonstrated that the chemotherapy drugs Gemcitabine and Oxaliplatin, induce tumour cells to release factors that stimulate dendritic cells which are themselves pivotal in stimulating T cell responses to tumours (see Cancer Vaccines Explained). It also shows that tumours may be made more visible to T cell attack after treatment with these drugs because they cause tumours to make more of the receptor that is recognised by T cells.
A collaboration of SGUL scientists has been funded to look at the effect of anti-malarial drugs on tumour cells. This work demonstrated the underlying biological effects of anti-malarial drugs. We also demonstrated beneficial effects of combining an anti-malarial drug and lenalidomide (a thalidomide-type drug) which itself is able to modulate immune responses Liu, 2010, and demonstrated the underlying mechanism responsible for the anti-tumour effect of some new anti-malarial compounds Gravett, 2010. One such anti-malarial, Artesunate, is currently in clinical trials for colorectal cancer and we are very keen to investigate potential immune effects of these drugs in colorectal cancer patients.
This is a new and interesting area of immunotherapy research which could ultimately benefit cancer patients in several ways. New approaches may be investigated for combined use of chemotherapy and immunotherapy in the clinic which may improve the clinical outcome of treatment. Furthermore, the stimulatory effects of these drugs on the immune system seems to occur in many cases at low concentrations. Thus clinical studies may investigate lower dose chemotherapy in combination with immunotherapy, and this may result in the reduction of characteristic side effects of chemotherapy on patients.
Maturation of dendritic cells
Two projects are currently funded which aim to improve our understanding of the best ways to promote dendritic cell stimulation.
The David Fine Memorial PhD studentship finished in October 2010. This work aims to understand events that occur during the death of tumour cells treated with two drugs that stimulate the immune system; double-stranded RNA (dsRNA) and Interferon-gamma. These drugs induce tumour cells to die, but more importantly the dying tumour cells influence the stimulation and maturation of dendritic cells. During the course of the work the following observations were made. (1) Not all tumour cells are susceptible to this treatment unless a further process is undertaken to get dsRNA into the cell (known as electroporation). (2) The dying tumour cells release a number of factors which may be important in influencing dendritic cell stimulation. (3) Dendritic cell take up dying tumour cells, an event that is likely to be important in promoting further immune responses by T cells.
The CVI provides funding for a post-doctoral scientist for one year to look for immune responses to tumour cells treated with dsRNA and interferon. This work is ongoing. Ultimately it is likely that this work can be translated to the clinic either in the form of a vaccine or using drugs, such as Hiltonol, that stimulate the immune system in a similar way (see future clinical trials).
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).
A project is underway which is designed to discover biomarkers detectable in the serum of melanoma patients treated with a dendritic cell vaccine. Preliminary results suggest that profiling a panel of proteins in the blood of vaccinated patients may predict which patients are more likely to respond to vaccine. This would mean that patients could be assigned to correct treatment groups and those with the correct profile would be more likely to benefit from their vaccine. In an attempt to validate these observations we collaborated with several other groups to secure samples from prostate cancer and melanoma patients undergoing similar immunotherapy. Although the results from these other trials are not identical there is a trend showing that non-responders have elevated inflammatory markers. This suggests that, in the context of patients with melanoma, pre-treatment with an anti-inflammatory agent may enhance responses to vaccines. Early studies suggest that this is the case. However, other exciting data has emerged from these collaborations, particularly the observation that Interleukin-15 may be found in greater amounts in prostate cancer patients who are likely to respond better to immunotherapy.
A further discovery arising from the melanoma DC vaccine trial is the finding that the profile of antibody subtypes in the serum may correspond to how well patients respond clinically to the vaccine. Although we do not yet understand what this signifies, this observation is unique and unexpected given the nature of the vaccine, and we are continuing with experiments to discover the significance of these findings.
This is a relatively new and exciting area of research within the cancer immunotherapy field and it is hoped that this work will result in better selection and treatment of patients in the future.
Gamma-delta cells
Gamma-delta T cells are known to have an important role in anti-tumour immunity. We believe that gamma-delta cells may also be a key player in immune responses to cancer treatments that are based on bacterial preparations such as BCG (which is used in bladder cancer) and Mycobacterium vaccae (an experimental treatment tested in melanoma and lung cancer). This project investigated the effects of mixing white blood cells with bacterial preparations. We observed that gamma-delta cells are stimulated and proliferate in response to the bacteria, but most importantly they become competent to kill tumour cells. These experiments are ongoing but may provide a fundamental understanding of the processes required to make gamma-delta cells kill tumours. The interest in gamma-delta cells will be expanded in planned clinical trials (see future clinical trials) to investigate (1) treatment of melanoma patients with Zometa and interleukin-2, and (2) the effect of a new Mycobacterium variant (M obuense) in melanoma patients, both of which are likely to be mediated in part by the activity of gamma-delta cells.
Observations on T regulatory cell numbers in colorectal cancer.
An MD student has been investigating the levels of T regulatory cells in patients with colorectal cancer. These cells are known to prevent immune responses in other cancers. Blood and tissue samples have been collected from patients at different stages of colorectal disease and an initial analysis of T regulatory cells in the blood has been done. The results of analysis broadly support the concept that more T regulatory cells are present in patients with advanced disease, which fits well with observations in other tumours backgrounds and correlates with the expected immune-suppression observed in cancer patients.
King’s College Studentship – external project.
This project, which was originally intended to be an 18 month post-doctoral position, has been converted to a studentship. It aims to investigate immune gene therapy in multiple myeloma. The potential of genetically modified acute myeloid leukaemia (AML) cells as an immunotherapeutic approach has previously been demonstrated. These cells are modified to produce two molecules with immune-stimulatory function; CD80 and IL-2. This is now being evaluated in a clinical trial in patients with poor prognosis AML. A significant potential for immune therapy has also been demonstrated in myeloma.
The project will investigate the use of AML cellular vaccine in this disease by
These studies are designed to demonstrate the therapeutic potential of this approach.
