Clinical outcomes of prexasertib monotherapy in recurrent BRCA wild-type high-grade serous ovarian cancer involve innate and adaptive immune responses
In: J Immunother Cancer, 2020
academicJournal
Zugriff:
BACKGROUND: Preclinical data suggest cell cycle checkpoint blockade may induce an immunostimulatory tumor microenvironment. However, it remains elusive whether immunomodulation occurs in the clinical setting. To test this, we used blood and fresh tissue samples collected at baseline and post therapy from a phase II trial of the cell cycle checkpoint 1 inhibitor (CHK1i) prexasertib in recurrent ovarian cancer. METHODS: Paired blood samples and fresh core biopsies, taken before treatment was started at baseline (cycle 1 day 1 (C1D1)) and post second dose on day 15 of cycle 1 (C1D15), were collected. To evaluate changes in the immune responses after treatment, multiparametric flow cytometry for DNA damage markers and immune cell subsets was performed on paired blood samples. RNA sequencing (RNAseq) of paired core biopsies was also analyzed. Archival tissue immune microenvironment was evaluated with immunohistochemistry. All correlative study statistical analyses used two-sided significance with a cut-off of p=0.05. RESULTS: Flow cytometric analysis showed significantly increased γ-H2AX staining after CHK1i treatment, accompanied by increased monocyte populations, suggestive of an activated innate immune response (median 31.6% vs 45.6%, p=0.005). Increased expressions of immunocompetence marker HLA-DR (Human Leukocyte Antigen DR antigen) on monocytes and of TBK1, a marker of STING (stimulator of interferon genes) pathway activation, in biopsies were associated with improved progression-free survival (PFS) (9.25 vs 3.5 months, p=0.019; 9 vs 3 months, p=0.003, respectively). Computational analysis of RNAseq data indicated increased infiltration of tumor niches by naïve B-cells and resting memory T-cells, suggestive of a possibly activated adaptive immune response, and greater T-reg infiltration after treatment correlated with worse PFS (9.25 vs 3.5 months, p=0.007). An immunosuppressive adaptive immune response, perhaps compensatory, was also observed on flow cytometry, including lymphodepletion of total peripheral ...
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Clinical outcomes of prexasertib monotherapy in recurrent BRCA wild-type high-grade serous ovarian cancer involve innate and adaptive immune responses
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Autor/in / Beteiligte Person: | Lampert, Erika J ; Cimino-Mathews, Ashley ; Lee, Joo Sang ; Nair, Jayakumar ; Lee, Min-Jung ; Yuno, Akira ; An, Daniel ; Trepel, Jane B ; Ruppin, Eytan ; Lee, Jung-Min |
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Zeitschrift: | J Immunother Cancer, 2020 |
Veröffentlichung: | BMJ Publishing Group, 2020 |
Medientyp: | academicJournal |
DOI: | 10.1136/jitc-2019-000516 |
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