Overcoming Resistance Mechanisms to Immune Checkpoint Inhibitors: Leveraging the Anti-Tumor Immune Response

As far back as 3000 years ago, the immune system was observed to play a role in mediating tumor regression. Since then, many strategies have been developed to leverage the anti-tumor immune response. However, while many patients respond to ICIs up front some do not, and many of those that do eventually experience tumor progression. Currently, there are several predictive biomarkers of the immune checkpoint inhibitor response; however, no one test appears to be universally predictive and their application varies by disease site. There are many ways in which cancer cells develop primary or acquired resistance to immune checkpoint inhibitors. Efforts to reverse resistance include ways to combat T cell exhaustion, reprogram the tumor microenvironment, increase the availability of tumor neo-antigens, target alternative immune checkpoints, restore a normal/healthy patient gut microbiome, oncolytic viruses and tumor vaccines. The most studied and most promising methods include combining ICIs with therapies targeting alternative immune checkpoints and restoring a normal/healthy patient gut microbiome. This review will discuss T cell-mediated immunity, how this is leveraged by modern immunotherapy to treat cancer and mechanisms of immune checkpoint inhibitor resistance, while highlighting strategies to overcome primary and secondary resistance mechanisms.