Abstract 5000: Cell cycle checkpoint kinase (CHK)1 inhibition induces immune modulation in recurrent <i>BRCA</i> wild-type high-grade serous ovarian cancer (HGSOC) patients
Authors: Erika J. Lampert, Min-Jung Lee, Jane B. Trepel, Akira Yuno, Ashley Cimino-Mathews, Joo-Sang Lee, Eytan Ruppin, Jayakumar Nair, Irene Ekwede, Jung-Min Lee
Journal: Cancer Research (2019)

Abstract Background: Data suggest cell cycle checkpoint inhibition with cyclin-dependent protein kinase 4 and 6 inhibitors may modulate the tumor immune microenvironment by augmenting T cell activation. It is unknown whether CHK1, which regulates the G2/M transition, may similarly engage in immune cross-talk. We hypothesize that CHK1 inhibition may increase tumor and peripheral immunogenicity via increased DNA damage and modulation of the innate and adaptive immune system in recurrent ovarian cancer. Methods: We previously reported clinical efficacy of the CHK1 inhibitor (CHK1i) prexasertib in heavily pretreated BRCA wild-type (BRCAwt) HGSOC patients, yielding a 33% response rate. Blood samples were collected at baseline and 6-24 hours post-second dose on cycle 1 day 15 (C1D15) to assess immune subsets and γ-H2AX using multiparametric flow cytometry. Paired fresh core biopsies were collected at baseline and post-treatment on C1D15 for total RNA-seq. Archival tissue samples were also obtained. Results: 23 of 24 patients had paired blood samples for correlative flow cytometry studies. There was a statistically significant increase in γ-H2AX from baseline to C1D15 in CD3+ and CD19+ lymphocytes (median fluorescence intensity 1.63 vs 1.74 p=0.034; 1.69 vs 1.76 p=0.040, respectively) suggesting increased DNA damage after CHK1i treatment. The percent of total CD14+ monocytes per mononuclear cells increased after treatment (31.6 vs 45.6% p=0.005), and an increase from baseline to C1D15 in HLA-DR on CD14+ monocytes, a marker of immunocompetence, was associated with improved PFS (3.5 months vs 9.25 months if decreased vs increased p=0.019). There was a significant decrease in CD4+ and CD8+ T cells on C1D15 compared to baseline (25 vs 19.6% p=0.008; 9.49 vs 7.63% p=0.005, respectively). However, GITR+ CD4+ and CD8+ T cells, suggesting activated effector T cells, increased on C1D15 (0.32 vs 0.82% p=0.0003; 0.23 vs 0.5% p&amp;lt;0.0001, respectively). Of the four The Cancer Genome Atlas molecular subtypes of HGSOC, immunoreactive was most common (7/18 [39%]) among 18 available pretreatment biopsies. Molecular subtype was not predictive of response and did not impact immunomodulatory effects seen. In 9 paired biopsies, there were no significant differences in expression levels of immunostimulatory (e.g. IFN-γ, IL-16) nor suppressive cytokines (e.g. IL10, TGF-β, CCL22). Immunohistochemical staining for PD-L1, Tregs, TILs, TAMs, and CD8 expression on archival tissue samples will be presented. Conclusions: CHK1i treatment increases γ-H2AX levels in peripheral blood indicating prexasertib-induced DNA damage. The data suggest CHK1 inhibition elicits an anti-tumor innate immune response in the peripheral blood of heavily pretreated BRCAwt HGSOC patients. An increase in immunocompetent monocytes may be associated with clinical benefit and warrants further evaluation. Citation Format: Erika J. Lampert, Min-Jung Lee, Jane B. Trepel, Akira Yuno, Ashley Cimino-Mathews, Joo-Sang Lee, Eytan Ruppin, Jayakumar Nair, Irene Ekwede, Jung-Min Lee. Cell cycle checkpoint kinase (CHK)1 inhibition induces immune modulation in recurrent BRCA wild-type high-grade serous ovarian cancer (HGSOC) patients [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 5000.