A major obstacle to cancer immunotherapy is overcoming tolerance to ‘self-antigens’. While the immune responses against foreign antigens are not susceptible to self-tolerance, those mounted against tumour-associated self-antigens are subject to suppression by central or peripheral tolerance mechanisms (1). In humans, T-cell receptors (TCRs) that recognize self-tumour antigens have a lower affinity for the major histocompatibility complex (MHC): peptide complexes, compared to their virus-specific TCR counterparts, due to the thymic elimination of high-affinity TCRs. Thus, the endogenous T-cell activity is inadequate for the control of cancer (1).
Tumours are frequently invaded by immune cells as part of the body’s response to malignant growth. Among these immune infiltrates, tumour-infiltrating lymphocytes (TILs) can be isolated from a patient’s tumour tissues, expanded ex-vivo to high numbers and adoptively transferred back into the patient to elicit a durable anti-tumour response (2). This has certain drawbacks - TILs need to be harvested during surgery, they may not be available in sufficient numbers for all cancers and they expand poorly in many cases (3).
Using tumour-specific TCRs enables the targeting of both membrane and cytoplasmic proteins. Unfortunately . . .