Ahmad A Tarhini, Fatima Iqbal

Enhancing or prolonging T-cell activation by monoclonal antibodies (mAbs) blocking negative signaling receptors such as CTLA4 is one approach to overcoming tumor-induced immune tolerance. Ipilimumab and tremelimumab inhibit CTLA4, prolonging antitumor immune responses and leading to durable anti-tumor effects. Treatment with these mAbs has demonstrated clinically important and durable tumor responses and disease control rates in patients with unresectable advanced melanoma. Durable objective responses have been reported across a spectrum of doses and schedules, with relative safety in this patient population. Although the phase III tremelimumab melanoma study was closed for "futility", the 1-year survival rate of >50% for tremelimumab and the median survival of 11.7 months (compared with 10.7 months for chemotherapy) are notable. Results of the phase III studies testing CTLA4-blockade with ipilimumab are eagerly anticipated. The further development of these agents includes testing in the neoadjuvant melanoma setting (ipilimumab) as well the adjuvant high-risk melanoma setting (ipilimumab). Future progress with CTLA-4 blockade therapy will also likely come from the use of combinations of agents that target several critical regulatory pathways of the immune system and modulate the immune response in the host in a synergistic and controlled fashion.