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Published on: June 12, 2021
Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer
Manuela Terranova-Barberio1, Nela Pawlowska1, Mallika Dhawan1
1Division of Hematology and Oncology, University of California, San Francisco, CA, USA.
Abstract:
Responses to immunotherapy are uncommon in estrogen receptor (ER)-positive breast cancer and to date, lack predictive markers. This randomized phase II study defines safety and response rate of epigenetic priming in ER-positive breast cancer patients treated with checkpoint inhibitors as primary endpoints. Secondary and exploratory endpoints included PD-L1 modulation and T-cell immune-signatures. 34 patients received vorinostat, tamoxifen and pembrolizumab with no excessive toxicity after progression on a median of five prior metastatic regimens. Objective response was 4% and clinical benefit rate (CR + PR + SD > 6 m) was 19%. T-cell exhaustion (CD8+ PD-1+/CTLA-4+) and treatment-induced depletion of regulatory T-cells (CD4+ Foxp3+/CTLA-4+) was seen in tumor or blood in 5/5 patients with clinical benefit, but only in one non-responder. Tumor lymphocyte infiltration was 0.17%. Only two non-responders had PD-L1 expression >1%. This data defines a novel immune signature in PD-L1-negative ER-positive breast cancer patients who are more likely to benefit from immune-checkpoint and histone deacetylase inhibition (NCT02395627).
Insights
Epigenetic priming with vorinostat, tamoxifen, and pembrolizumab shows potential for ER-positive breast cancer. A novel immune signature may predict benefit in PD-L1-negative patients receiving immunotherapy and histone deacetylase inhibitors.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Immunotherapy response is limited in estrogen receptor (ER)-positive breast cancer.
- Predictive biomarkers for immunotherapy in ER-positive breast cancer are lacking.
Purpose of the Study:
- To evaluate the safety and response rate of epigenetic priming combined with checkpoint inhibitors in ER-positive breast cancer.
- To identify immune signatures associated with treatment benefit.
Main Methods:
- A randomized phase II study involving 34 ER-positive breast cancer patients.
- Patients received vorinostat, tamoxifen, and pembrolizumab.
- Analysis of PD-L1 expression, T-cell exhaustion markers, and tumor lymphocyte infiltration.
Main Results:
- Objective response rate was 4%, and clinical benefit rate was 19%.
- No excessive toxicity was observed.
- A specific T-cell exhaustion and regulatory T-cell depletion signature was associated with clinical benefit in PD-L1-negative patients.
Conclusions:
- Epigenetic priming with vorinostat, tamoxifen, and pembrolizumab is safe and shows activity in heavily pretreated ER-positive breast cancer.
- A novel immune signature involving T-cell exhaustion and regulatory T-cell modulation may predict response to combined epigenetic and immune checkpoint inhibition in PD-L1-negative ER-positive breast cancer.
