Abstract 4024: Epigenetic priming potentiates immune checkpoints inhibitors in ovarian cancer
Authors: Qing Yu , Condello Salvatore , Meyer Katie J. , Caperell-Grant Andrea , Nephew Kenneth P. , Matei Daniela 
Published: July 2016

Abstract
Background: Ovarian cancer (OC) progression is accompanied by the establishment of stable and transcriptionally repressive epigenetic modifications. An important mechanism of immune evasion is represented by epigenetic silencing of tumor antigens (NY-ESO-1, Muc16 and MAGE). We hypothesize that by reversing DNA methylation, DNA methyl transferase inhibitors (DNMTIs) restore the expression of such antigens, potentiating anti-tumor immune response. The targeting of immune checkpoints regulated by programmed cell death protein-1(PD-1) signaling represents a novel therapeutic strategy in cancer, including in OC. Here we set out to measure the anti-tumor effects of epigenetic priming in combination with PD-1/PDL-1 blockade in OC preclinical models.
Methods: The ID8 intraperitoneal (ip) immunocompetent syngeneic mouse model was used to measure the effects of the novel DNMTI guadecitabine (SGI-110, Astex Pharmaceuticals Inc) and PDL1 blockade. The experimental groups consisted of non-specific IgG (control), guadecitabine 2mg/m2 sq bi-weekly, murine anti-PDL1 inhibitory antibody (10mg/kg) bi-weekly and combination of guadecitabine with anti-PDL1 antibody (n = 6 mice/group, 3 week treatment). Immune cells collected from the ascites and spleens of tumor bearing mice were either directly processed or co-cultured with ID8 cells for 48 hours. Cells were immuno-phenotyped by flow cytometry. In OC cells treated with guadecitabine, changes in gene expression were analyzed by real time-PCR.
Results: In ID8 tumors bearing mice, the combination of PDL1 blockade with guadecitabine significantly decreased primary tumor formation (P&lt;0.05) and malignant ascites accumulation (P&lt;0.0001) compared with the control group. Treatments were well tolerated without detectable weight changes attributable to toxicity. CD8+ cell fractions expressing the exhaustion markers (PD1+ or CTL4+) isolated from the ascites and spleens of control mice were diminished by guadecitabine, PD-L1 inhibitory antibody, and the combination treatment. Guadecitabine and the combination regimen increased CD8+/MHC1+ and CD8+/CD40+ cell populations. Treatment with DNMTIs significantly increased the expression of tumor antigens Muc16, Mage A2, A11, and NY-ESO 1 (p&lt;0.01) in several OC cell lines.
Conclusions: Guadecitabine in combination with anti-PDL1 antibody induced striking anti-tumor effects in an immunocompetent OC syngeneic model by activating cytotoxic T-cells. These data support clinical strategies utilizing epigenetic priming using DNMTI in combination with immune checkpoints inhibitors.
Citation Format: Yu Qing, Salvatore Condello, Katie J. Meyer, Andrea Caperell-Grant, Kenneth P. Nephew, Daniela Matei. Epigenetic priming potentiates immune checkpoints inhibitors in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4024.