Immune activation in patients with locally advanced cervical cancer treated with ipilimumab following definitive chemoradiation (GOG-9929)

Clin Cancer Res. 2020 Aug 18;clincanres.0776.2020. doi: 10.1158/1078-0432.CCR-20-0776. Online ahead of print.

Abstract

Purpose: A Phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune modulation therapy with the checkpoint inhibitor ipilimumab (anti-CTLA4) following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunological and viral correlates were assessed before, during, and after treatment.

Experimental design: Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T cell subsets were evaluated by multi-parameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot.

Results: Expression of the activation markers ICOS and PD-1 significantly increased on T cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T cell populations. Genotype-specific E6/E7-specific T cell responses increased post-CRT in 1/8 HPV16+ patients and in 2/3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL-6, IL-8) post-CRT were significantly associated with worse progression-free survival.

Conclusions: Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of anti-tumor immune cell function after primary CRT for this population at high-risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.