Chimeric Antigen Receptors (CAR) are genetically engineered molecules specifically designed to redirect immune cells, typically αβ T lymphocytes, against antigens expressed on the surface of tumour cells. The CAR is designed in a modular fashion, and comprises an extracellular antigen binding domain (usually part of an antibody), a spacer region that links it to the transmembrane region and an intracellular signalling domain that transmits an activation signal to the cell upon antigen recognition. Identification of an antigen by a CAR engineered T cell results in its activation, proliferation and will initiate signals to attack and destroy the cancer cells.
CAR engineered T cell are one of the most promising therapies to fight cancer and a number of clinical trials have demonstrated the applicability of the approach, especially targeting B cell malignancies. However, most of the existing CAR-T technologies are subjected to “on-target, off-tumour” dangerous side effects caused by the inability of the engineered T cell to distinguish between healthy and cancerous cells expressing the targeting antigen. Therefore, CAR-T technology is encumbered by the need for truly-restricted tumour associated antigens i.e. antigens which are expressed only on tumour cells and not on healthy cells. This feature limits the range of tumours to which the CAR-T technology may be applied.
TCB used Gamma delta T cells as a platform for the CAR technology, taking advantage of their inherent specificity against phosphoantigens, which are expressed only by cancerous and infected cells, to develop ImmuniCAR®. TCB have rationally designed a CAR which provides an activation signal only with concurrent activation of the Gamma delta TCR. This ensures that the cytotoxic effect of the CAR-expressing Gamma delta T cell will be focused on the pathogenic cells expressing the target antigen whilst ignoring healthy cells. This is ensured by the fact that when the target antigen is expressed on a healthy cell, the Gamma delta CAR-T cell is not activated. This technology enables the targeting of cell surface antigens which have been previously been deemed ‘undruggable’ due to their expression on healthy/non diseased tissue. Thus, ImmuniCAR® has the potential to treat a wider range of tumours than can be targeted with present strategies.
Advantages of ImmuniCAR® over current CAR-T approaches include:
- Increase in safety due to absence of off-tumour effects.
- Broad range of antigens that can be targeted
- Simple manufacture process
- Enhanced potency over non-transduced Gamma delta T cells
- Reduced possibility of resistance due to the bispecific nature of ImmuniCAR® (CAR and phosphoantigens)