Epigenetic priming enhances anti-tumor immunity in resistant ovarian cancer [RNA-Seq]

Here we describe the clinical and biological activity of guadecitabine, a second generation HMA, given in a low dose as a priming strategy before pembrolizumab, a humanized anti-PD1 antibody in a clinical trial for patients with recurrent, platinum resistant ovarian cancer. The methylomic and transcriptomic effects of the combination demonstrate readily activation of the anti-tumor immunity. High dimensional immune profiling of periferal mononuclear cells (PBMCs) and tumor biopsies obtained before and after treatment show distinct immune profiles and tissue architectural features associated with clinical benefit. Our study provides an in-depth view of the immune milieu of platinum resistant ovarian cancer and of the effects of the combination of HMAs and pembrolizumab on the interactions between immune cell populations and tumor cells. This was a non-randomized open-label two stage phase II trial testing guadecitabine and pembrolizumab in recurrent platinum-resistant OC. Patients all had epithelial ovarian, fallopian tube or primary peritoneal cancer that had recurred or progressed <6 months after their last dose of platinum-based chemotherapy. Guadecitabine (G) 30 mg/m2 was administered by subcutaneous (sc) injection on days 1 - 4 of a 21-day cycle. On day 5 pembrolizumab 200 mg was administered intravenously (iv). Each cycle was 21 days. The drug combination was given until progression of disease or unacceptable toxicity. Imaging-guided tumor biopsies, ascites, or blood for determining cytokine response and collection of PBMCs were obtained from consenting patients at specific timepoints. Three 18-gauge tumor cores were obtained on C1D1 (day 1 of cycle 1) and C2D8 (day 8 of cycle 2) and the material was immediately snap frozen (~25-50mg/specimen). C1D1 and C2D8 tumor samples were obtained from 11 patients (total of 22 samples). When available, ascites or pleural fluid was centrifuged and fluid and cell pellets were separated prior to cryo-preservation.