Abstract 272: Synergistic activity of the ATR inhibitor BAY1895344 in combination with immune checkpoint inhibitors in preclinical tumor models
Authors: Antje Margret Wengner, Dennis Kirchhoff, Lars Roese, Sandra Berndt, Gerhard Siemeister, Bertolt Kreft, Dominik Mumberg
Journal: Cancer Research (2019)

Abstract The DNA damage response (DDR) consists of complex signaling pathways that secure the integrity of the genome in eukaryotic cells. Numerous lines of evidence suggest that enhanced DNA damage caused by intrinsically or acquired defects in DDR, increases tumor immunogenicity, potentially impacting anti-tumor immune responses and sensitivity to immune checkpoint inhibition. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in DDR by activating essential signaling pathways of DNA damage repair and is the key mediator of the replication stress response being indispensable for cellular proliferation and viability. Inhibition of ATR has been shown to lead to impaired cell cycle progression, increased DNA damage and replication stress ultimately resulting in rapid cellular lethality. The potential of combining inhibition of ATR with immune checkpoint blockade was studied in preclinical tumor models. We assessed efficacy of the novel ATR inhibitor (ATRi) BAY 1895344 in monotherapy and in combination with anti-PD-1 (Programmed Death 1) or anti-PD-L1 (Programmed Death 1 Ligand 1) antibody in syngeneic tumor models in immunocompetent mice. Interestingly, depletion of CD8+ T cells strongly reduced single agent activity of BAY 1895344 in the C57BL/6 mouse colorectal cancer (CRC) model MC38. Along this line, synergistic anti-tumor activity of BAY 1895344 and anti-PD-1/ PD-L1 could be demonstrated in MC38 tumors as well as in the BALB/c CRC model CT26 (both anti-PD-1/ PD-L1 sensitive), and the lymphoma model A20 (anti-PD-1/ PD-L1 insensitive). Remarkably, the synergistic activity was only achieved by sequential dosing of combination partners in the schedule: 1) anti-PD-1/PD-L1 Q2W (days 1 and 4 each week) followed by 2) BAY 1895344 BID 3 days on/ 4 days off (days 5, 6, 7 each week). Concomitant application or sequential dosing in the reverse order did not result in synergy or was even antagonizing single agent-mediated anti-tumor effects. Potential mechanisms underlying the interplay of ATRi and immune system activation will be discussed. Overall, our data suggest that the combination of immune checkpoint inhibitors and ATRi BAY 1895344 may enhance the anti-tumor efficacy of each single agent and potentially re-sensitize tumors to immune oncology treatments. BAY 1895344 is currently under clinical investigation in patients with advanced solid tumors and lymphomas as single agent (NCT03188965). Clinical exploration of a combination with anti-PD-1 is warranted. Citation Format: Antje Margret Wengner, Dennis Kirchhoff, Lars Roese, Sandra Berndt, Gerhard Siemeister, Bertolt Kreft, Dominik Mumberg. Synergistic activity of the ATR inhibitor BAY1895344 in combination with immune checkpoint inhibitors in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 272.