21P - Mass cytometry reveals a population of exhausted CD8+ T cells associated with durvalumab/tremelimumab/vinorelbine efficacy in advanced cervical cancer (iMOVIE).

Background

Immune checkpoint inhibitors (ICI) were recently developed in advanced cervical cancer (CC). However, the efficacy of ICI monotherapy is limited and predictive biomarkers of ICI efficacy are scarce. To improve ICI efficacy in advanced CC, a promising strategy is to combined anti PD(L)-1, anti CTLA-4 and chemotherapy. Our objective is to discover immune circulating biomarkers in patients with metastatic CC in ≥2nd line, treated with anti PD-L1 and anti CTLA-4 in combination with metronomic oral vinorelbine (MOV).

Methods

Three immune panels of up to 40 markers were developed to explore the immune landscape (T cells, NK cells and myeloid cells) of advanced cervical cancer in liquid biopsy. We used high-dimensional mass cytometry (CyTOF) in baseline blood samples from patients with advanced CC treated with durvalumab/tremelimumab and MOV. CyTOF datas were analyzed by machine-learning algorithms for dimensionality reduction, automated clustering and candidate prediction. Immune candidates were confirmed by manual gating. Maxstat and log-rank test were used to determine optimal cut-off and compare groups, respectively.

Results

From the cervix cohort of the phase 1/2 MOVIE multicentric prospective clinical trial (NCT03518606, sponsor UNICANCER France), 29 patients were analyzed. Median age was 56 years old. Compared to healthy donors, CC patients presented a decrease of CD4⁺CD127⁺TCF1⁺ T cells and an increase in CD8⁺TIGIT⁺ T cells. In CC patients treated in MOVIE trial (durvalumab, tremelimumab and MOV), clustering analyses, machine-learning analyses and manual gating confirmation identified a population of exhausted and senescent CD8⁺ T cells (CD8⁺CD45RA⁺CCR7^-TIGIT⁺CD57⁺) associated with treatment efficacy. An optimal cut-off at 0.95% of CD45⁺ cells was determined. Patients with a high percentage of CD8⁺CD45RA⁺CCR7^-TIGIT⁺CD57⁺ T cells had an improved clinical benefit rate (p=0.005), an improved PFS (HR=0.35, CI95, 0.13-0.95, p=0.013) and an improved OS (HR=0.23, CI95, 0.08-0.69, p<0.001).

Conclusions

This study identified a population of exhausted and senescent CD8⁺ T cells associated with response and survival with dual ICI and MOV in advanced cervical cancer.

Legal entity responsible for the study

Unicancer France.

Funding

GIRCI PACA.

Disclosure

All authors have declared no conflicts of interest.