| Popis: |
Background: PARP7 is a mono-ART that is upregulated in response to cellular stress (e.g., viral infection, cigarette smoke), and suppresses the Type I interferon (IFN) response following cytosolic nucleic acid sensing. RBN-2397 is a first-in-class PARP7 inhibitor, inducing cancer cell autonomous and immune stimulatory effects in preclinical models through enhanced Type I IFN signaling in cancer cells. Moreover, RBN-2397 induces CD8 T cell-dependent tumor-specific immune memory in an immunocompetent mouse cancer model [1]. RBN-2397 is currently being tested in an ongoing Phase I clinical study (NCT04053673) [2]. Here we present evidence of proof of mechanism in the paired biopsies of tumors from Phase 1 patients. Methods: Plasma CXCL10 from patients was measured by MSD while ISG expression in PBMCs was measured by NanoString. Baseline and on-treatment patient tumor biopsies were analyzed by NanoString, CD8/GZMB IHC, and MIBI-TOF to characterize immune changes in the tumor microenvironment. Results: In peripheral blood from patients treated with RBN-2397, neither plasma nor PBMC CXCL10 increased more than 2-fold over baseline. Expression of 42 ISGs was not consistently induced in a dose-dependent manner in PBMCs. However, in tumor types of interest (e.g., cancers of the upper aerodigestive tract), CXCL10 expression increased, with similar effects observed for a subset of ISGs in multiple evaluable paired biopsy samples. Confirming preclinical studies [1], increases in CD8 T cell infiltration along with induction of granzyme B expression were observed in several evaluable paired patient tumor biopsies by immunohistochemistry. Using the MIBI-TOF technology, we observed up to 50-fold increases in intratumoral activated T cells as well as monocytes and M1 macrophages, most strikingly in two NSCLC patients. Conclusions: In patients treated with RBN-2397 pharmacodynamic effects were preferentially observed in tumor tissue relative to the periphery, including an increase in immune infiltration into the tumor microenvironment. These data provide evidence for induction of an adaptive immune response and confirm the tumor-intrinsic, immunomodulatory mechanism of action of RBN-2397 in patients. References: 1. Gozgit et al. PARP7 negatively regulates the Type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Cancer Cell. 2021 2. Falchook et al. A First-In-Human Phase 1 Study of a Novel PARP7 Inhibitor RBN-2397 in Patients with Advanced Solid Tumors. ASCO 2021 oral presentation Citation Format: Kristy Kuplast-Barr, Melissa L. Johnson, Manish R. Patel, Timothy A. Yap, Gerald S. Falchook, Patricia LoRusso, Ryan Abo, Chang Liu, Erika L. Manyak, Lisa Cleary, Viviana Bozon, Sudha Parasuraman, Heike Keilhack, Kristen McEachern. RBN-2397, a novel, potent, and selective PARP7 inhibitor, induces tumor-intrinsic type I interferon responses and adaptive immunity in patient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1836. |
