Evaluation of immune cell-specific functional response following single or combinatorial treatment with DNA damaging and immunotherapy agents using patient-derived immunocompetent cultures of High Grade Serous Ovarian Cancer

Abstract

High Grade Serous Ovarian Cancer (HGSOC) is one of the most lethal gynaecological malignancies with a 5-year survival rate of less than 42%. Current treatment regimens against the disease include debulking surgeries, Neo Adjuvant Chemotherapy, and Poly (ADP-ribose) polymerase inhibitors. Immunotherapies have shown very little promise with regards to this disease. Here as part of a prospective clinical trial (OncosysOVA - NCT06117384), we use patient derived immunocompetent cultures (iPDCs) to test the efficacy and immune cell (CD8+ T cell, CD4+ T cell and CD11c+ T cell) functional activation using the markers : GrzB, IFNγ, Ki-67, HLA-DR upon treatment with a DNA damaging drug - Berzosertib/ VE-822 (ATRi) and novel immunotherapy drug - Ziritaxestat/ GLPG1690 (ATXi) drugs and their combination. Already established drugs such as Olaparib (PARPi) and Pembrolizumab (Anti-PD1-antibody) were used to validate the results obtained from the ATRi and ATXi treatments. The results showed that increased concentrations of both ATRi and ATXi are harmful for the immune cells and decreased the functional activity of these cells. A combination of ATRi 0.1 μM + ATXi 0.2 μM increased tumour cell death without having a pronounced immune cell death, while ATXi 0.2 treatment showed the highest immune cell activation. Most results were patient specific which adds more evidence to the usage of iPDCs for studying immune cell activity in the tumour infiltrated immune cells and as a pre-clinical tool to determine the treatment regimen and dosage for each patient.