Tumor cells predominantly express
self-antigens and overcoming self-tolerance is the primary challenge to effective
immunotherapy.
Tumors also express
ligands for co-inhibitory molecules on immune cells, in order to suppress anti-
tumor immunity. Over a decade ago, the first
antibodies generated to block the co-inhibitory molecule CTLA-4 was tested in patients with metastatic
melanoma. Results from this landmark trial have informed not only the current landscape of checkpoint blockade but also the way in which
immunotherapy trial outcomes are determined.
Antibodies targeting PD-1 and its
ligand, PD-L1, soon followed and use of these checkpoint inhibitors (ICIs) have expanded exponentially. ICI treatment has shown long-lasting clinical benefit in several
tumor types and patients refractory to other treatments can often respond to ICI
therapy. On the other hand, in some
tumor types, the response to ICI is short-lived and
tumors eventually recur. Current clinical trials are focused on enhancing anti-
tumor effects through combinations of multiple ICIs with agents which cause
tumor death, particularly in solid
tumors, in order to enhance antigen presentation. It is also important to define which patients will respond to
therapy with ICIs as over half of all patients suffer from immune-related adverse events (irAE), some of which are severe and long-lasting.