Induction of Sensecence Using Dexamethasone to Re-sensitize NSCLC to Anti-PD1 Therapy
Status:
Recruiting
Trial end date:
2025-01-31
Target enrollment:
Participant gender:
Summary
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.
Phase:
Phase 1/Phase 2
Details
Lead Sponsor:
VA Office of Research and Development
Collaborators:
Barbara Ann Karmanos Cancer Institute University of Michigan Wayne State University