In the continued analysis of immunological responses to acute myeloid leukaemia (AML) cells that are genetically modified to express CD80 and IL-2, we have shown that these cells can induce the in vitro activation of AML specific, autologous T cell isolated from relapsed patients (Hardwick et al., Cancer Immunology Immunetherapy 2010). The specificity of the induced cytolytic activity against AML blasts, rather than normal bone marrow cells, has received a great deal of national and international public attention.

ECMC has supported the expansion of production capacity in the Rayne Cell Therapy Suite (RCTS), a GMP facility granted manufacturing authorization by MHRA for the production of cell and gene therapy based investigational medicinal products (MA-IMP) products. Over the past year RCTS has produced cell and viral vectors for the following clinical trials:

• In vitro differentiated dendritic cells, presenting either two class-I, or two class-I and two class-II hTERT peptides, for new Phase-I clinical trials that are based at Queens Medical Centre (Nottingham) and United Lincolnshire Hospital NHS Trust (Professor Lindy Durant and Oleg Eremin).
• A lentivirus vector encoding CD80 and IL-2 for a first-in-man Phase-I clinical trial in immune gene therapy of acute myeloid leukaemia; a first-in man study based King’s College Hospital (Professor Ghulam Mufti).
• A retrovirus vector encoding HSV-tk for a first-in-man Phase I clinical trial based at the Institute of Child Health and Great Ormond Street Hospital, for the genetic modification of donor T cells in order to control graft vs host disease (Professors Boby Gaspar and Adrian Thrasher).

A large collaboration has been set up with a leading international pharmaceutical company for the analysis of antibody dependent cellular cytotoxicity (ADCC), particularly in response to a new class of antibodies that have been bioengineered for optimal induction of ADCC. In collaboration with Paul Ross at Guys and St Thomas' NHS Trust, analysis of natural killer (NK) cells isolated from 65 colorectal cancer patients with post-chemotherapy relapse, and an age matched panel of controls demonstrated: i) loss of functional competence in NK cells isolated from post-chemotherapy relapsed colorectal cancer patients, and ii) the ability of even the post-chemotherapy NK cells to mount effective ADCC in response to a panel of bioengineered (ADCC optimised) antibodies. These studies have underpinned two first-in-man clinical trials that have been initiated.

Since December 2009, 65 new patients have been reviewed in the phase I clinic and 32 enrolled on studies. In its two full years of operation the Unit recruited to 9 trials, and in 2010 will begin to use new infrastructure provided by the Clinical Research Facility at Guy’s Hospital. Studies recently completed include:

• An antibody-based immunotherapy that showed efficacy in malignant melanoma in a first-in-man trial (‘A phase I study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma or renal cell carcinoma’ Spicer J et al., presented at ASCO Annual Meeting June 2009).
• A new generation erbB inhibitor demonstrating marked activity in lung cancer (‘Activity of BIBW 2992, an oral irreversible EGFR/HER2 dual kinase inhibitor, in combination with weekly paclitaxel in non-small cell lung cancer’ Stavridi F et al., presented at World Conference on Lung Cancer,San Francisco, August 2009).
• An oncolytic virus in combination with chemotherapy

Novel agents in ongoing trials include small molecule kinase inhibitors and a monoclonal antibody. Preclinical development of a novel therapeutic antibody strategy developed at KCL (MOv18 IgE) continues in development, supported by the CRUK Drug Development Office.

The clinical work of the Cancer Early Phase Trials Unit is complemented by funding for laboratory staff funded through the KCL/UCL Comprehensive Cancer Imaging Centre and the Comprehensive Biomedical Research Centre. A preclinical multidisciplinary programme in antibody drug development is focussing on the discovery of novel antibodies for the treatment of melanoma, and the development of techniques for in vivo SPECT imaging of labelled antibodies in preclinical and clinical trials. Conjugation of MOv18 IgG with DTPA and 111-In chelation has been achieved with maintenance of antibody specificity, and this work will next be extended to MOv18 IgE, which should soon be available in GMP-quality and clinically useful quantity.

We are continuing to study precursor lesions such as DCIS where better prediction of likely behaviour will facilitate more accurate selection of treatment for patients. To date, 2mm tissue microarrays have been manufactured in triplicate from over 250 cases of pure DCIS reviewed from the Breast Tissue and Data Bank and these have been assessed with a large range of antibodies including hormone receptors, HER2, basal cytokeratins, EGFR and proliferation markers. Optimisation of DNA extraction and amplification procedures for these same precursor lesions is underway in order to enable us to correlate the morphological appearances and immunoproflie with genomic changes and with patient outcome.

The KCL ECMC, under the umbrella of the Integrated Cancer Centre, operates two HTA licensed tissue banks to support our research portfolio. ECMC support for staff associated with these activities has enabled over 1300 samples from more than 670 patients to be collected during the course of 2009. Through the auspices of the various access committees that operate to enable distribution of samples for research, there have been approximately 30 applications during this period that have all been accommodated.

Thoracic tissue banking started on 1st January 2009 within the GST-RTDB structure, collecting frozen tissue, fixed-paraffin tissue and blood. To date 46 tumour samples have been frozen, 133 have fixed, paraffin tissue and 125 matched blood. Applications to access material in the thoracic bank will be considered in 2010”.The regional thoracic surgical service (now 5 full time thoracic surgeons) is located on the Guy’s site. Frozen material, from both open biopsy and endobronchial ultra-sound guided transbronchial needle aspiration, is stored on the Guy’s site. Clinical data on thoracic oncology patients is stored on a fully electronic case record/database system.

The melanoma team have identified from patients antibodies immuno-reactive with melanomas. These are currently being worked through a pre-development selection programme.