1114 Immunotherapeutic activity of OX425 against PD-1 resistant HR⁺HER2^-breast cancer

BackgroundHormone receptor (HR)+ breast cancer is a cold tumor that responds poorly to immune checkpoint blockers targeting PD-11,2, calling for the development of therapeutic strategies that inflame the HR+ tumor microenvironment to restore PD-1 sensitivity. OX425 is a second-generation poly(ADP)-ribose polymerase 1 (PARP1)-targeting decoy oligonucleotide (ODN) that drives PARP1 hyperactivation coupled to exhaustion of the DNA damage response, ultimately killing cancer (but not normal) cells as a function of metabolic breakdown.3 PARP1-targeting decoy ODNs have been shown to mediate multiple immunostimulatory effects, standing out as promising combinatorial partners for PD-1 blockers in cold tumors.3MethodsWe harnessed a unique endogenous mouse model that recapitulates key immunobiological features of human HR+HER2- breast cancer, as driven by subcutaneous, slow-release medroxyprogesterone acetate (MPA) pellets combined with 7,12-dimethylbenz[a]anthracene (DMBA) gavage4, to investigate the therapeutic efficacy of OX425 delivered intraperitoneally 1X or 2X per week at 100 or 500 µg/mouse, optionally combined with a mouse PD-1 inhibitor (delivered intraperitoneally in 2 doses of 200 µg/mouse 3 days apart from each other). Tumor growth, mouse-adapted RECIST score assessments, progression-free survival, overall survival and other clinically relevant parameters were monitored until ethical endpoint.ResultsOX425 at the highest dose (500 µg/mouse 2X per week) was associated with weight loss across treated mice (irrespective of PD-1 blockage) and premature mortality in 10% of the mice, calling for dose reduction to 100 µg/mouse 2X per week. At all other administration schedules, OX425 was well tolerated, effective at controlling tumor growth and extending overall survival in mice bearing MPA/DMBA-driven carcinomas (which are intrinsically resistant to PD-1, similar to HR+ breast cancer in women).1,2,4 Blocking PD-1 increased the therapeutic activity of OX425 when delivered 2X per week at 100 µg/mouse as it inhibited the development of secondary tumors.ConclusionsOX425 at doses < 500 µg/mice 2X per week is well tolerated in mice and mediates single-agent immunotherapeutic activity in models of PD-1-resistant HR+HER2- breast cancer, with a potential for synergy with PD-1. Further investigation of the immunostimulatory and therapeutic properties of OX425 is warranted.ReferencesEmens LA. Breast Cancer Immunotherapy: Facts and Hopes. Clin Cancer Res. 2018;24(3):511–520. Rugo HS, Delord JP, Im SA, Ott PA, Piha-Paul SA, Bedard PL, Sachdev J, Le Tourneau C, van Brummelen EMJ, Varga A, Salgado R, Loi S, Saraf S, Pietrangelo D, Karantza V, Tan AR. Safety and antitumor activity of pembrolizumab in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Clin Cancer Res 2018;24(12):2804–2811. Wael Jdey, Chloe Doizelet, Claudia Galassi, Christelle Zandanel, Veronique Trochon-Joseph, Vincent Hayes, Marie-Christine Lienafa, Giulia Petroni, Lorenzo Galluzzi. Anticancer effects of PARP1 hyperactivation by a decoy oligodeoxynucleotide in vitro and in vivo. Journal of Clinical Oncology. 2022;40:e15060. doi:10.1200/JCO.2022.40.16_suppl.e15060. Buqué A, Bloy N, Perez-Lanzón M, Iribarren K, Humeau J, Pol JG, Levesque S, Mondragon L, Yamazaki T, Sato A, Aranda F, Durand S, Boissonnas A, Fucikova J, Senovilla L, Enot D, Hensler M, Kremer M, Stoll G, Hu Y, Massa C, Formenti SC, Seliger B, Elemento O, Spisek R, André F, Zitvogel L, Delaloge S, Kroemer G, Galluzzi L. Publisher Correction: Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat Commun. 2020;11(1):4787.Ethics ApprovalThis study was approved by Weill Cornell Medicine IACUC.