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Neoadjuvant and adjuvant pembrolizumab for advanced high-grade serous carcinoma (NeoPembrOV): A randomized phase II GINECO clinical trial

ABSTRACT: PD-1/PD-L1 blockade did not show survival benefit in high grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial and by combining RNA-seq and multiplexed immunofluorescence stainings, we explored the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment and identified parameters correlating to response. 1) The combination therapy resulted in a significant increase of intraepithelial CD8+PD-1+ T cells that correlated to clinical benefit. 2) High CD8B/FOXP3 and high CD8B/ENTPD1 ratios were significantly associated with response to NACT+P, while KDR and VEGFR2 expression were associated with resistance. 3) Combining endothelial and monocyte signatures and the CD8B/FOXP3 ratio predicted response to NACT+P with an AUC of 0.93 (95% CI 0.84–1.00). These results indicate that targeting regulatory T cells and endothelial cells, especially VEGFR2+ endothelial cells, could overcome ovarian cancer immune resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227666 | GEO | 2024/02/26

REPOSITORIES: GEO

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Project description:PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and arrayCGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort ovarian cancer patients. Concentration-dependent anti-proliferative effects of PD-0332991were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, Rb, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration and time dependent manner, and enhanced the effects of chemotherapy. Rb proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and associated with adverse clinical outcome (progression free survival, adjusted relative risk 1.49, 95%CI 0.99-2.22, p =0.054). PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer. Gene expression of 40 individual ovarian cell lines relative to an ovarian cell line reference mix containing equal amounts of 41 ovarian cell lines (including OCC-1 which was later identified as originating from mouse). The expression data was correllated with cell line growth response to CDK 4/6 inhibitor PD-0332991 to identify genes associated with drug sensitivity and resistance.

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Neoadjuvant and adjuvant pembrolizumab for advanced high-grade serous carcinoma (NeoPembrOV): A randomized phase II GINECO clinical trial

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