Targeting Immunological Synapse: New Horizons In Immunotherapy for Cancer

摘要

Immunotherapy has been a part of armamentarium against neoplastic diseases for decades. Various approaches have been used with a very limited success. The site of the contact between a T cell and an antigen-presenting cell (APC) is named the immunological synapse, and it is characterized by an organized spatial redistribution of TCR-pMHC complexes and accessory molecules. For the last 10 years, several accessory molecules have been discovered and their function in T-cell stimulation has been described. The list includes co-stimulatory molecules (CD28, CD27, OX-40, 4-1BB, ICOS, CD40L) and inhibitory molecules (CTLA-4, PD-1, PD-2, BTLA). This knowledge led to the development of a new area in the immunotherapy for cancer-targeting the immunological synapse. Monoclonal antibodies blocking CTLA-4 are in advanced clinical testing; and 6-21% response rates have been observed in patients with metastatic melanoma with few relapses. Treatment with CTLA-4-blocking antibodies demonstrated the ability to break tolerance to self antigens, manifested by the development of side effects in the form of autoimmune diseases. Agonistic antibodies against CD40 have undergone phase I testing, and they showed activity in non-Hodgkin lymphoma and melanoma. Antibodies against 4-IBB, PD-1, and OX-40 are at earlier stages of clinical testing. After these antibodies have been tested as monotherapy, combination of two or three agents targeting accessory molecules appears to be a direction for future development.