Innovative strategies to light up the fire into cold tumors and improve the benefit of anti-PD-1 based immunotherapy
Cancer immunotherapy based on Immune Checkpoint Blockades (ICBs), exemplified by the anti-programmed death 1 antibody (anti-PD-1), has emerged as a ground-breaking treatment for many cancers and is now in the process of fundamentally reshaping the treatment of cancer. Nevertheless, this enthusiastic vision has been seriously challenged by the clinical data reporting that not all patients benefit from the remarkable clinical remissions achieved by ICBs. A substantial number of them reap a short-term benefit or no benefit at all. To extend the benefit of immunotherapy, immuno-oncology research is now pushing towards pairing various ICBs or combining immunotherapy with other anti-cancer therapies. Numerous ICB combinations, evaluated in clinical trials to extend the therapeutic benefit of anti-PD-1, showed moderate minimal survival benefit associated with heavy toxicities. Evidence suggests that effective combination approaches should not be restricted to pairing several ICBs, but also associating small molecules inhibiting key pathways in cancer cells themselves or immunosuppressive factors in the tumor microenvironment. Indeed, the immune landscape status of tumors, which differentiates “cold” immune desert tumors that are not responding to ICBs and “hot” inflamed immune infiltrated tumors that are responding to ICBs, is one of the major characteristics predicting the response to ICBs. In this seminar, I will present some pathways and strategies that we have identified and established to reprogram the tumor immune landscape and switch “cold” to “hot” tumors. I will also provide the preclinical proof of concept on how to improve the benefit of ICBs by combining small molecules targeting key pathways in tumor cells and the tumor microenvironment.