Immunologic checkpoint blockade with drugs that target the CTLA-4 and PD-1/PD-L1 checkpoint pathway have demonstrated significant promise in a variety of malignancies; harnessing of one’s own immune system has shown a tremendous scope for a varirty of cancers and has revolutionized the way we approach cancer treatment.
Initial efficacy of these agents in melanoma paved the way to their use in a variety of other cancers. Several Pd-1/PD-L1 agents are approved across several cancers after demonstration durable clinical responses and a very favorable safety profile. There has been an avalanche of checkpoint inhibitor trials and combining novel immunologic agents with other immunologic agents or targeted therapies is the next rational step to improve outcomes patient outcomes. There is an impetus to compare immunotherapeutic agents with standard of care chemotherapy in 1st line and well as refractory setting.
However, many patients are primarily resistant to immune checkpoint blockade –based monotherapy and many others will eventually relapse. As we start utilizing more of immunotherapeutic agents as standard of care and part of clinical trials, we need to think about potential resistance and developing novel combinations. Besides the B7 co-inhibitory receptors, OX40 (CD134), 4-1 BB (CD137) are co-stimulatory molecule can be expressed by activated immune cells and trials are ongoing with drugs targeting these alone or in combination with checkpoint inhibitors. In addition, there are novel intratumoral agents like TLR7/8 agonists, which are being tested in trials.
This is indeed a very exciting era for revolutionizing the cancer therapy paradigm and rapid advances are being made with novel immunotherapeutic combinations.