Beyond checkpoint inhibitors: the three generations of immunotherapy

Anti-tumor immunotherapy was rediscovered and rejuvenated in the last two decades with the discovery of CTLA-4, PD-1 and PD-L1 and the roles in inhibiting immune function and tumor evasion of anti-tumor immune response. Following the approval of the first checkpoint inhibitor ipilimumab against CTLA-4 in melanoma in 2011, there has been a rapid development of tumor immunotherapy. Furthermore, additional positive and negative molecules among the T-cell regulatory systems have been identified that that function to fine tune the stimulatory or inhibitory immune cells and modulate their functions (checkpoint modulators). Many strategies are being explored to target macrophages, NK-cells, cytotoxic T-cells, fibroblasts, endothelial cells, cytokines and molecules involved in tumor tolerance and microbiome. Similar to agents that target checkpoint modulators, these newer targets have the potential to synergize with other classes of immunotherapeutic agents and importantly may overcome the resistance to other immunotherapies. In order to better understand the mechanism of action of all major classes of immunotherapy, design clinical trials taking advantage of different types of immunotherapeutic agents and use them rationally in clinical practice either in combination or in sequence, we propose the group all immunotherapies into three generations: with CTLA-4, PD-1 and PD-L1 inhibitors as the first generation, agents that target the checkpoint modulators as the second generation, while those that target TME as the third generation. This review discusses all three generations of immunotherapy in oncology, their mechanism of actions, major clinical trial results and indication, strategies for future clinical trial designs and rational clinical applications.