18 new early phase trials opened in 2009 (13 phase I/II/POM, 3 biomarker and 2 Phase III with ECMC component). A further 16 are currently in set-up. The total number of open trials has now increased to 75. Of note is that 44 of these are trials in which UCL is the Lead Centre. An additional 1065 patients are reported this year as being recruited to ECMC studies at UCL.

A very wide range of disease types are represented in the trials including a significant number of trials in rare tumours such as brain, sarcoma and neuroendocrine. Particular expertise continues to grow in therapies directed against specific pathways, cell surface targets and tumour stroma, in addition to strengths in immunological therapies and treatment of haematological malignancies.

CHT25 is a chimeric antibody to the IL2 receptor, CD25 labelled with 131-iodine. The therapy was designed from our previous studies showing the benefit of sustained exposure of tumour to antibody for optimising therapy. This was achieved by using the long biological half life of a chimeric antibody matched to a radionuclide with a correspondingly long physical half life. The resulting CRUK phase I trial in patients with Hodgkin and T cell lymphoma was reported in 2009 (Dancey et al. Clinical Cancer Research 15(24);7701-7710) and showed a 67% response rate at the MTD. Dosimetry studies confirmed the predicted prolonged retention of radiolabeled antibody in tumour and showed that response depended on the amount of radioactivity administered. One of the patients who had all failed conventional therapies remains in complete remission after 2 1/2 years. A phase II trial is in set up by CR-UK and will include ECMCs in Manchester and Southampton. CHT25 has potential as an effective new treatment for Hodgkin and T cell lymphoma.

Despite improved outcome from chemotherapy and bone marrow transplantation (BMT), the major cause of treatment failure for acute myeloid leukaemia (AML) is relapse. Wilms’ tumour antigen 1 (WT1) is a tumour-associated antigen that is over-expressed in leukaemia cells compared to normal tissue. We, and others, have demonstrated that T cell responses can be directed towards WT1 and in the laboratory such T cells are capable of killing primary leukaemia cells and leukaemia-forming cells (CFU progenitor cells and LTC-IC stem cells) whilst not affecting the function of normal bone marrow stem cells. A Phase I trial at UCL is exploring peptide vaccination with a vaccine containing two separate MHC class I restricted peptide epitopes derived from the WT1 protein (pWT126 and pWT235) as a new treatment option for patients with AML. The principal research question, out with establishing the safety and toxicity profile, is to determine whether peptide vaccination can induce self-restricted autologous T cell responses against WT1 peptides, and if so, whether the immunological responses are durable. Secondary objectives are to document evidence of clinical efficacy. This study recruited 8 adult patients with poor risk acute myeloid leukaemia (AML). Data has been collected and analysis of immune responses performed.

The results of two UCL ECMC studies in the area of stem cell transplantation were reported recently: (i) Cytomegalovirus-specific T cell immunotherapy promotes restoration of durable functional antiviral immunity following allogenic stem cell transplantation (Peggs KS et al Clinical Infectious Diseases 2009;49:1851-60). The data from this single-arm open-label phase II study confirm the ability of cellular immunotherapy to hasten reconstitution of antiviral immunity following allogenic transplantation, indicating that significant clinical benefit may be conferred in terms of reduction of secondary viral infection episodes, potentially reducing exposure to the toxicities of antiviral drugs. (ii) Phase I study of high-stringency CD8 depletion of donor leukocyte infusions after allogenic hematopoietic stem cell transplantation (Orti G et al Transplantation 2009 88(11):1312-8). The conclusions are that graft-versus-tumour effects can be observed after high-stringency CD8-depleted donor leukocyte infusions, although the major toxicity remains graft-versus-host disease in this high-risk patient group. The safety and efficacy profile of this approach will require testing in a randomised controlled study.

Data standards are being developed to facilitate data sharing and integration in various aspects of experimental medicine such as genomics and clinical data. There is a need to integrate these diverse data types in order to follow the translational cycle effectively and safely and so that different research areas can communicate consistently. We have developed Guidelines for Information About Therapy Experiments (GIATE) for this purpose. It is based on the NCI Thesaurus and caBIG common data elements which provide data standards across the relevant spectrum of research. GIATE adds to this by providing a high level structure which links data elements across the field of therapy development from target discovery through development of a therapeutic to investigation in molecular, cellular, animal model and clinical experiments. A systems-based approach can thus be achieved, facilitating design and planning of experiments, collaboration and data sharing. Safety can be enhanced by helping to identify gaps or inconsistencies in data and orderly and complete data can be presented in a consistent manner for reports and regulatory purposes. GIATE has been adopted by the Antibody Society, is available on the web (http://www.genscript.com/giate-viewer/index.php) through a collaboration with Genscript Ltd and has been published (Yong M et al; Protein Eng Des Sel. 2009 Mar;22(3):221-4.). Further developments are in hand in collaboration with the NCRI Informatics Initiative with a view to providing related tools for other ECMCs.

We have previously established histone H2AX phosphorylation as a molecular pharmacological marker of DNA interstrand crosslink cancer chemotherapy in vitro. We have now successfully used this assay as a research endpoint on two Phase I studies (CR-UK and NCI) of the novel DNA minor groove cross-linking agent SJG-136 in both lymphocytes and tumour cells. This was the first demonstration of this assay to measure DNA damage response to a cross-linking drug in a clinical trial context. The assay has now been fully validated and is incorporated as a pharmacodynamic endpoint in two Phase II studies of this drug in 2010.