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
3630 - Results of phase 1 clinical trial of high doses of Seleno-L-methionine (SLM) in sequential combination with Axitinib in previously treated and relapsed clear cell renal carcinoma (ccRCC) patients
Presenter: Yousef Zakharia
Session: Poster Display session 3
Resources:
Abstract
2356 - Safety and Efficacy of CDX-014 , an Antibody-Drug Conjugate against T Cell immunoglobulin mucin-1 (TIM-1), in advanced Renal Cell Carcinoma
Presenter: Bradley McGregor
Session: Poster Display session 3
Resources:
Abstract
1028 - SPAZO2 (SOGUG): Outcomes and prognostic significance of IMDC intermediate prognosis subclassification in metastatic renal cell carcinoma (mRCC) in patients treated with 1st-line pazopanib (1stPz).
Presenter: Begona P. Valderrama
Session: Poster Display session 3
Resources:
Abstract
2293 - Effect of Antacid Intake on the Therapeutic Efficacy of Sunitinib (SUN) in Metastatic Renal Cell Carcinoma (mRCC) Patients (pts): a Sub-Analysis of the STAR-TOR Registry
Presenter: Katrin Schlack
Session: Poster Display session 3
Resources:
Abstract
1451 - Randomized phase 3 trial of avelumab + axitinib vs sunitinib as first-line treatment for advanced renal cell carcinoma: JAVELIN Renal 101 Japanese subgroup analysis
Presenter: Motohide Uemura
Session: Poster Display session 3
Resources:
Abstract
4399 - Overall and progression-free survival according to MSKCC scores in 1st line sunitinib treatment of metastatic renal cell carcinoma (mRCC)
Presenter: Jindrich Finek
Session: Poster Display session 3
Resources:
Abstract
1344 - Combination therapy with checkpoint inhibitors for first-line treatment of advanced renal cell carcinoma: A systematic review and meta-analysis of randomized controlled trials
Presenter: Kyaw Thein
Session: Poster Display session 3
Resources:
Abstract
3462 - A phase II trial of TKI induction followed by a randomized comparison between nivolumab or TKI continuation in renal cell carcinoma (NIVOSWITCH)
Presenter: Viktor Grünwald
Session: Poster Display session 3
Resources:
Abstract
5268 - Nivolumab (N) treatment beyond progression in a real-world cohort of patients (pts) with metastatic renal cell carcinoma (mRCC)
Presenter: Sophie Hans
Session: Poster Display session 3
Resources:
Abstract
4235 - First results of safety profile of nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in II and III line of patients (pts) with metastatic renal cell carcinoma (mRCC) in NIVES Study
Presenter: Cristina Masini
Session: Poster Display session 3
Resources:
Abstract