Immunotherapy clinical trials

Induction of Sensecence Using Dexamethasone to Re-sensitize NSCLC to Anti-PD1 Therapy

Lung cancer accounts for 30% of all cancers among American war Veterans and remains the leading cause of cancer related deaths. Half of all lung cancers are metastatic non-small cell lung cancer (NSCLC), with a 2-year survival rate of 10%. Immunotherapy with immune checkpoint inhibitors (ICI) has emerged as a promising therapeutic strategy that aims to harness the immune system to fight lung cancer. However, given the modest response rates of 20-25% to these immune checkpoint inhibitors, there is a greater desire to extend their benefits to more patients. Along with the desire to extend their benefits, there is a critical need for the development of novel approaches that can expand the benefit from immune checkpoint inhibitors and create more durable responses, prolonging survival from lung cancer. The investigators' studies show that extended dexamethasone (Dex) treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in glucocorticoid receptor (GR) overexpressing lung adenocarcinoma (AC) cell populations. Further, following withdrawal of Dexamethasone, proteins associated with the senescence associated secretory phenotype (SASP) strongly attracted and expanded T-cells, NK cells and monocytes stimulated tumor cell cytolytic activity of NK cells. Therefore, dexamethasone may induce a persistent senescence phenotype in tumor cell sub-populations expressing moderate/high levels of GR and resultant chemokines produced by the senescent cells will mobilize host immune cells to reboot response to immune checkpoint inhibitors following complete Dexamethasone withdrawal.