Induction of Senescence using Dexamethasone to re-sensitize NSCLC to anti-PD1 therapy

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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 ICIs and the desire to extend their benefits to more patients, there is a critical need for the development of novel approaches that can expand the benefit from ICIs and create more durable responses, prolonging survival from lung cancer. Our 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 cell populations. Further, following withdrawal of Dex, proteins associated with the senescence associated secretory phenotype (SASP), particularly CCL2, CCL4, CXCL1 and CXCL2 strongly attracted and expanded T-cells, NK cells and monocytes and stimulated tumor cell cytolytic activity of NK cells. Our overarching hypothesis is that in lung AC patients who are not on baseline steroids, pre-treatment with Dex will induce a persistent senescence phenotype in tumor cell sub-populations expressing moderate/high levels of GRα and resultant chemokines produced by the senescent cells will mobilize host immune cells to reboot response to ICI following complete Dex withdrawal. We will test this hypothesis through the conduct of the following aims. Specific Aim 1: Use FLT-PET imaging and blood analysis to test whether a 7-14 day pre-treatment of lung AC patients with Dex followed by Dex withdrawal will induce persistent senescence related cell cycle arrest in ≥ 1 lesion in ≥ 60% of patients, (based on GRα expression) accompanied by release of SASP proteins and activation of T and NK cells. Specific Aim 2: Test whether a 7-14 day pre-treatment of lung AC patients with Dex followed by Dex withdrawal and subsequent re-challenge with pembrolizumab will yield an overall response rate (ORR) of ≥ 33% to pembrolizumab in association with tumor GR status, SASP and immune cell activation. These aims will be conducted through a Phase II clinical trial designed as a single-arm two-stage study in Veterans whose lung AC has progressed on ICI. Based on our preliminary data, we expect that Dex will induce tumor senescence in at least one lesion in ≥ 60% of patients and secondarily improve overall response to pembrolizumab by 33%. Success with these aims would inform a larger study that could potentially change the way we approach patients with primary or acquired resistance to ICIs with an off the shelf medication that could re-sensitize lung AC to ICIs. Our proposed research could substantially benefit Veterans with metastatic NSCLC, a group with the most genomically complex lung cancers and poor survival.