Antigen-specific co-stimulation to enhance the anti-tumour activity of TCR gene modified cytotoxic T lymphocytes

The immune system can protect individuals against virus infection and against the growth of certain types of tumours. Some human cancers are caused by viruses, which allows the immune system to recognise and eliminate the virus-infected cancer cells. Killer cells of the immune system are particularly important for this elimination, as they possess receptor molecules that allow them to specifically recognise and kill infected cancer cells.
Unfortunately, many human cancers are not caused by virus infection and therefore do not contain virus-derived markers that are recognised by killer cells. As a consequence, killer cells cannot efficiently recognise and kill such cancer cells.
In this project we will gene modify killer cells such that they can efficiently recognise human cancer cells. We will introduce into killer cells the genes coding for two receptors that specifically recognise markers that are present in various human cancer cells. In this way, the killer cells can use two receptors and simultaneously recognise two markers present in cancer cells, which should result in efficient cancer cell killing.

Although TCR gene transfer can readily produce populations of antigen-specific T lymphocytes for adoptive cancer immunotherapy, tumour cell recognition usually occurs in the absence of co-stimulation, which may result in poor T cell stimulation in vivo. In this project we will test whether dual receptor T cells can efficiently recognise co-stimulation-deficient tumour cells. The TCR, specific for HLA presented tumour peptides will deliver signal I, while the co-stimulation signal II is delivered by chimeric single chain antibodies specific for a molecule expressed on the surface of tumour cells.
Here, we will use a chimeric single chain antibody construct that specifically binds to CD19, a marker expressed in most human B-cell malignancies. The intracellular domain of the construct has been engineered and harbours the signalling motif of CD28. The simultaneous engagement of the tumour-specific TCR and the anti-CD19 co-receptor will deliver two signals that are expected to synergise and improve T cell avidity, the production of IL2 and proliferation of effector T cells. If successful, the antigen-specific co-stimulation concept is highly versatile and can be extended to other single chain antibodies in combination with the signalling motifs of various co-stimulatory molecules such as CD27, CD28, CD134 (OX40) and CD137 (4-1BB).