Engineering T cells for cancer therapy
Although natural T cells can be effective, only limited numbers of tumour-specific T cells are found in cancer patients and controls in the immune system mean that expanding those in the presence of extensive cancer can be difficult.
Expanding natural cancer-specific T cells for use in adoptive immunotherapy can be more effective than other types of cancer immunotherapy, but deriving large numbers of specific T cells is a complex and difficult issue. An attractive alternative is to use gene transfer to endow normal peripheral blood T cells with tumour-targeting capabilities and to expand these specific T cells to large numbers before using them in therapy.
These 'engineered T cells' can be targeted in a number of ways. An interesting approach is to couple antibody type recognition to T cell signalling. The gene-immunotherapy group has extensively explored this approach to targeting carcinoembryonic antigen found in many gastrointestinal tract tumours and CD19 (found on B cell tumours). Trials of these methods are underway. Importantly, this genetic engineering of T cells also allows us to manipulate other T cell signalling pathways such as the costimulatory receptors (Figure 1).
For further information, see: Engineered T cells against B cell malignancies
Figure 1:
Illustration of the natural T-cell receptor (TCR) and various forms of engineered receptors. The main signalling chain in the TCR is the z chain and this can be linked to several antigen recognition domains and fused with other signalling regions such as the CD28 receptor.
Adoptive engineered T cell Targeting to Activate Cancer Killing (ATTACK)
This approach to cancer immunotherapy is problematic and to optimally develop the system requires broad-ranging immunological and technological expertise. To facilitate this development the group is co-ordinating a European Union project with 16 partners comprising many of the leading European groups in this field. This project, named ATTACK, commenced in 2005 and over the five years should lead to major advances in the field.
For further information, see: ATTACK
GMP cell therapy facilities
A key to undertaking trials of cell therapy is the ability to manipulate and grow T cells to very high standards in order to avoid potential contamination. Such GMP facilities need professional management and the gene-immunotherapy group has developed one in conjunction with the National Blood Service at the Manchester Blood Centre. It is planned that this facility will be replaced by one on the Christie site. The facility will handle processing of haematopoietic stem cells for conventional transplantation as well as more novel forms of cell therapy.