Immunology in the clinic review series; focus on cancer: double trouble for tumours: bi-functional and redirected T cells as effective cancer immunotherapies

Abstract

Cancer is one of the most important pathological conditions facing mankind in the 21st century, and is likely to become the most important cause of death as improvements continue in health, diet and life expectancy. The immune response is responsible for controlling nascent cancer through immunosurveillance. If tumours escape this control, they can develop into clinical cancer. Although surgery and chemo- or radiotherapy have improved survival rates significantly, there is a drive to reharness immune responses to treat disease. As T cells are one of the key immune cells in controlling cancer, research is under way to enhance their function and improve tumour targeting. This can be achieved by transduction with tumour-specific T cell receptor (TCR) or chimaeric antigen receptors (CAR) to generate redirected T cells. Virus-specific cells can also be transduced with TCR or CAR to create bi-functional T cells with specificity for both virus and tumour. In this review we outline the development and optimization of redirected and bi-functional T cells, and outline the results from current clinical trials using these cells. From this we discuss the challenges involved in generating effective anti-tumour responses while avoiding concomitant damage to normal tissues and organs.

Fig. 1

Representation of a conventional T cell receptor in comparison with a basic chimeric antigen receptor (CAR). The CAR is composed of linked V chains from a tumour-associated antigen (TAA)-specific monoclonal antibody, bound to a spacer arm from the hinge region of immunoglobulin (Ig)G or from the CD8 receptor. This then attaches to a CD28 transmembrane domain (TM) [–25]. The cytoplasmic domain is composed of the CD3-ζ signalling element, although other elements may also be included, such as CD28 and 4-1BB motifs which give improved activation and survival [–25].

Fig. 2

Bi-functional T cells can be generated by (1) isolating donor virus-specific T cells then (2) expanding them in vitro[41]. These T cells can then be (3) transduced either with tumour-specific T cell receptors (TCRs) or chimeric antigen receptor (CAR), expanded and returned to the donor [41]. The endogenous TCR recognition of virus via antigen-presenting cells (APC) maintains survival and (4) enhances anti-tumour activity of the transduced T cells [41,42].