B180
Preclinical development strategy to obtain regulatory approval for a Phase 1 trial using adoptive transfer of autologous T-cells expressing the chimeric immune receptor MFE23-CD3ζ in patients with advanced carcinoembryonic antigen positive malignancies
Nigel Westwood1, Robert Williams1, David Gillam2, Fiona Thistlethwaite2, Robert Hawkins2, Ryan Guest3, Eric Austin3, Keith Smith4
1Cancer Research UK, London, UK, 2University of Manchester, Manchester, UK, 3NHS Blood and Transplant, Manchester, UK, 4NHS Blood and Transplant, Cambridge, UK
Carcinoembryonic antigen (CEA) is an oncofoetal antigen, which shows limited expression in adult tissues. CEA expression is however found in many common tumour types including colorectal, gastric and pancreatic cancers. Therapeutic immune-based strategies targeting CEA have been explored over recent years and although well tolerated these approaches have failed to elicit effective anti-tumour clinical responses. Adoptive transfer of T-cells expressing gene products targeting specific tumour antigens is emerging as a novel and promising approach to cancer treatment. The current Phase I clinical trial uses autologous T-cells that have been genetically modififed via retroviral transduction to express a chimeric immune receptor protein comprised of MFE-23, a single chain anti-CEA antibody, and the signal-transducing domain of CD3ζ to target and selectively kill CEA positive tumour cells.
Adoptive T-cell therapies do not fit into standard toxicological testing schema. Non-clinical safety data supporting the regulatory application for the trial have been generated from studies using gene-modified T-cells introduced into immunocompromised mice. No adverse events were observed. Other data supporting the application have been derived from clinical studies targeting CEA by a variety of approaches, clinical experience with adoptive T-cell transfer and consideration of risks associated with retroviral gene transfer. As MFEz T-cells were considered high risk the data package for the trial received MHRA and expert scientific review (Commission on Human Medicines). Approval was granted in May 2007, with the first patient recruited in November 2007. Experience gained from the MFEz trial will facilitate the development of complex first-in-man trials within the UK.
