Scientists/Clinicians
Pre-Clinical Laboratory Research
The CVI provides funding for clinical trials and basic research aimed at improving cancer vaccines. Professor Angus Dalgleish’s group is comprised of several different groups which have a wide range of interests. The following passages give a brief synopsis of the work currently being carried out in his laboratory and the collaborations being used by CVI funded scientists to research cancer vaccines.
Dendritic cells
Prof Dalgleish’s group is investigating the best way of loading dendritic cells when there is no known tumour antigen. Although collaborative studies are planned which use RNA pulsed dendritic cells (sarcoma trial) future trials funded at the St George’s site will primarily use tumour lysate pulsed dendritic cells. To this end Dr Natalie Wilson, a CVI funded postdoctoral scientist, is optimising the immunological assays and readouts for these studies and her team is engaged in research to determine the most optimal loading and maturation conditions to be used in these trials. Publications from this work are expected in 2007.
CVI funded scientists work closely with a group funded by the Fischer Family Trust who are working on basic dendritic cell biology. Dr Mark Bodman-Smith and his group are working on aspects of dendritic cell maturation and migration. Their work indicates that apoptotic tumour cells act to stimulate the maturation of dendritic cells either through release of soluble factors or through direct uptake of tumour cell (possibly apoptotic bodies). Research done by Katie Lowe, a CVI funded PhD student, will aim to discover the nature of these soluble factors. Knowledge gained in this field will be of use in the future design of maturation protocols for dendritic cells in clinical trials.
Dr Bodman-Smith’s group is also investigating the effect of the TLR7 (Toll-like Receptor 7) agonist Aldara on dendritic cell migration. The results of these studies indicate that treatment with Aldara prevents dendritic cell migration to lymph nodes possibly due to an upregulation of adhesion molecules on the endothelium. Future work will attempt to explain these data and to determine the effect of Aldara on T cell activation. A CVI funded clinical trial run by Miss Debbie Green (a Clinical Research Fellow) has tested the efficacy of topically applied Aldara cream and systemic IL-2 on cutaneous melanoma. Her work shows that 80% of cutaneous and 50% of subcutaneous lesions respond to this treatment. Immunological monitoring has shown an increase in T cell activation and gamma-IFN production in Aldara treated patients. Early results from this trial are encouraging with 10 out of 12 patients displaying a positive clinical response.
Studies will also be carried out on the effects of Mycobacterium vaccae which is believed to stimulate TLRs on dendritic cells. It is possible that the adjuvant effect of using M vaccae in the maturation of dendritic cells will improve the formulation of dendritic cell vaccines.
Modifying Immune System Regulators
In addition to cancer vaccines Prof Dalgleish’s lab are very interested in drugs which will modulate the immune system and synergise with immunotherapy. A major point of control in the immune response generated by vaccines is through T regulatory cells. Their purpose is to damp down immune responses to foreign agents so that the immune system does not damage normal body tissue. To be able to switch these cells off, even for a short period of time, is one of the major goals of immunotherapists. There are a number of drugs which are capable of doing this which are currently in clinical trials. One such drug family that has this activity is Thalidomide. Prof Dalgleish’s group have been working with Celgene Corporation of America who manufactured a variety of analogues or similar molecules screened to eliminate the birth defect side effect of Thalidomide. Fortunately this has been possible and the resulting drugs are more active than Thalidomide. Recently Prof Dalgleish has published work using these analogues for solid tumour and myeloma.
The future of dendritic cell vaccines at St George’s
Close collaboration of scientific groups working at St George’s under the leadership of Prof Angus Dalgleish is delivering a firm foundation for the development of improved dendritic cell vaccines. In the future the CVI hopes to expand its contribution to basic laboratory research at St George’s leading to improvements in vaccine design and immunological monitoring. It is hoped that Prof Dalgleish’s work will lead to a better understanding of dendritic cell vaccines and that CVI funded clinical and scientific work will benefit both the wider scientific community and cancer patients alike.
The Cancer Vaccine Institute (CVI) is currently recruiting for the following clinical trials. If you would like to find out about how to refer patients please click here.
Childhood Cancers
Professor Dalgleish has collaborated with John Anderson from Great Ormond Street and put in a formal grant to the CRUK to apply dendritic cell vaccine therapy to adolescent tumours. Funding for this project has been awarded and the CVI is funding staff and consumables at the St George’s site to treat patients over 10 years old. The trial will recruit 30 patients with relapsed or malignant osteosarcoma over a three year period. Consequently it may be possible to treat over half the patients in the UK who develop these tumours. Three patients in a pilot study on an ‘informed consent’ basis have already been treated, the second of which had a dramatic response which was maintained for over a year.
Prostate Cancer
The CVI previously supported phase I trials of a whole cell vaccine for prostate cancer. The success of these initial trials has led to a phase IIb clinical trial on hormone resistant advanced prostate cancer which is currently recruiting. For further information go to www.onyvax.com and follow links to clinical trials."
Brain Cancer
During 2007 we hope to start a vaccine trial for brain cancer. Further information will follow.
Closed Trials
Cancer Vax Study - Stage IV melanoma
As previously reported, stage III recruitment has finished but we are receiving many referrals for stage IV and have commenced two new patients already this month. It should be noted that for every patient that goes on the stage IV study, we work up three or four who are found to have more aggressive disease than anticipated at the time of referral. These patients are being offered dendritic cell vaccine, if practical and appropriate. Arranging the work up for these trials can take the majority of a research nurses time, arranging and chasing up on all the screening, especially with regards to the tight time intervals involved.
Aldara/low dose IL-2 for subcutaneous disease / topical treatment metastatic melanoma and other cancer
We have identified the potential for Aldara, an ointment developed for the treatment of genital warts, to stimulate dendritic cells which are involved in anti tumour activity. Very exciting responses have led to a fully structured trial using the ointment applied directly to tumours in conjunction with low dose Interleukin-2. This led to the most spectacular responses that we have seen with a new study, showing that 80% of superficial melanoma lesions respond to this treatment and 50% of deeper lesions also respond (in press in the British Journal of Dermatology). Immunological studies have shown that this does not induce memory and therefore does not affect the immune response to tumours which have not been primed with the Aldara.
Dendritic Cell Vaccine Trial for Malignant Melanoma
MDC-2: A Phase I/II Study of allogeneic melanoma cell/autologous dendritic cell vaccine, in combination with IL-2 and with PGE2 suppression, in the treatment of patients with metastatic melanoma refractory to other treatments.
This trial is for patients, aged 16-85 years, with histologically proven stage IIIc (including two or more palpable lymph nodes, extracapsular or in-transit metastases) or stage IV (M1a = lymph node, subcutaneous or lung) melanoma that is not eligible for curative surgery, who have been off interferon treatment and chemotherapy for at least one month.
It started in August 2004 and over thirty melanoma patients with aggressive stage IV disease, who had failed chemotherapy, have been treated. Patients who are otherwise fit and well have a longer survival time than those treated by other therapies. Even patients who have progressed through maximum chemotherapy have responded with stable disease and increased quality of life and have had prolonged stabilisation of their disease.This is very similar to the results of colleagues in Europe and America. When the trial ends all results will be published and another trial will commence to further improve the significance and durability of responses to dendritic cell vaccines involving the following approaches: increasing the effectiveness of dendritic cells, removing regulatory cells that damp down immune responses and increasing the effectiveness of the T cells that kill cancers. In addition to improvements in therapeutic protocol a sub-group of patient will be selected who will benefit significantly from this treatment or to apply a combination therapy based on the biology of their disease.
