Abstract 3391
Background
Ovarian cancer prognosis is strongly dependent on the development of an anti-tumour immune response. However, tumours can epigenetically silence immunostimulatory genes in order to evade this response. We investigated whether a novel dual inhibitor of Ehmt2/Ezh2 methyltransferases (HKMT) was able to derepress expression of critical chemokines and augment immune responses in a murine ovarian cancer model.
Methods
ID8 Trp53-/- murine ovarian cancer cell line was previously generated, using CRISPR-Cas9 technique. Mice bearing intraperitoneal Trp53-/-tumours were treated with the novel Ehmt2/Ezh2 inhibitor, HKMTI-1-005, for 14 days (21-35d). Tumours were harvested for immune cell phenotyping by flow cytometry. HKMT1-1-005 was screened in vitrofor its ability to enhance expression of 84-chemokine genes in ID8 Trp53-/- ovarian cancer cells.
Results
In vitro, HKMTI-1-005 treatment significantly (p < 0.05) upregulated the expression of cxcl10 (3-fold), cxcl9 (22-fold) and ccl5 (14-fold), after stimulation with IFNγ. Mice treated with HKMTI-1-005 had longer survival (52 vs45d, p<.0001), less ascites (3.7 vs5.6ml, p=.0037) and trended towards tumour size reduction (weight 138 vs178mg, p=.10) compared to vehicle treatment. Tumours harvested 24hr post last HKMTI-1-005 dose had significantly more effector CD8+T cells (p=.03), natural killer (NK) cells (p<.0001) and dendritic cells (DCs, p=.02), and less naïve CD8+T cells (p=.02) and immunosuppressive CD4+Tregs (p=.02). Expression of the Cxcl9/Cxcl10 receptor Cxcr3 was increased in HKMTI-1-005-treated cohort tumours on CD8+[mean fluorescence intensity (MFI) 3959 vs2097, p<.0001], CD4+(MFI 2341 vs1099, p<.0001)and NK (MFI 1507 vs440, p<.0001) cells.
Conclusions
Inhibition of Ehmt2/Ezh2 HKMTs stimulates expression of chemokines involved in T cell, NK and DC recruitment. In vivo, HKMTI-1-005 alters the immune microenvironment and confers a small survival benefit. This suggests that HKMTI-1-005 could augment the anti-tumour immune response of current immunotherapies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Imperial College London.
Funding
Has not received any funding.
Disclosure
P. Spiliopoulou: Honoraria (self): BMS; Travel / Accommodation / Expenses: Nucana. I.A. McNeish: Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Takeda; Advisory / Consultancy: Tesaro; Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.
Resources from the same session
3611 - Phase II trial of SM 88 in Non-Metastatic Biochemical Recurrent Prostate Cancer.
Presenter: Benjamin Gartrell
Session: Poster Display session 3
Resources:
Abstract
2492 - A phase 1 study of Ad5 PSA/MUC-1/Brachyury Vaccine in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)
Presenter: Marijo Bilusic
Session: Poster Display session 3
Resources:
Abstract
3142 - Multicenter Phase I Trial of a DNA Vaccine Encoding the Androgen Receptor Ligand Binding Domain (pTVG-AR, MVI-118) in Patients with Metastatic Prostate Cancer
Presenter: Douglas McNeel
Session: Poster Display session 3
Resources:
Abstract
4327 - Impact of germline mutations in Homologous Recombination (HR) genes on the response to Radium-223 for metastatic castration resistant prostate cancer (mCRPC)
Presenter: Elena Castro
Session: Poster Display session 3
Resources:
Abstract
3600 - Serum biomarkers of bone metabolism in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with Radium-223 (Ra223): Results from a prospective multicentre study
Presenter: Nuria Romero Laorden
Session: Poster Display session 3
Resources:
Abstract
3742 - Prognostic value of tumor suppression genes (TP53, PTEN, Rb) in metastatic hormone sensitive prostate cancer
Presenter: Miguel Gonzalez Velez
Session: Poster Display session 3
Resources:
Abstract
2643 - Germline sequencing of advanced prostate cancer patients in the BARCODE2 trial
Presenter: Sarah Benafif
Session: Poster Display session 3
Resources:
Abstract
4349 - Impact of treatment sequence in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): data from the prospective PROREPAIR-B study.
Presenter: Carlo Cattrini
Session: Poster Display session 3
Resources:
Abstract
3301 - Implications of Single Nucleotide Polymorphisms (SNPs) in Androgen Related-Genes in Outcome of metastatic castration-resistant prostate cancer (mCRPC) patients treated with Abiraterone (Abi) and Enzalutamide (Enza)
Presenter: Isabel Aragon
Session: Poster Display session 3
Resources:
Abstract
2275 - Activating mutations in AKT1/PIK3CA are associated with poor clinical outcomes in metastatic prostate cancer (mPC)
Presenter: Simon Fu
Session: Poster Display session 3
Resources:
Abstract