Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929)
Diane M Da Silva, Danielle M Enserro, Jyoti S Mayadev, Joseph G Skeate, Koji Matsuo, Huyen Q Pham, Heather A Lankes, Katherine M Moxley, Sharad A Ghamande, Yvonne G Lin, Russell J Schilder, Michael J Birrer, W Martin Kast, Diane M Da Silva, Danielle M Enserro, Jyoti S Mayadev, Joseph G Skeate, Koji Matsuo, Huyen Q Pham, Heather A Lankes, Katherine M Moxley, Sharad A Ghamande, Yvonne G Lin, Russell J Schilder, Michael J Birrer, W Martin Kast
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-CTL antigen-4 (anti-CTLA-4)] 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, immunologic and viral correlates were assessed before, during, and after treatment.
Patients and methods: 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 multiparameter 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 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was 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 antitumor 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.
Trial registration: ClinicalTrials.gov NCT01711515.
Conflict of interest statement
Disclosure of Potential Conflicts of Interest
DMD, DME, JGS, HQP, HAL, and WMK have no conflicts to disclose. JSM is a consultant for Varian Medical Systems and reports receiving honoraria and travel reimbursement from AstraZeneca. KM reports receiving honoraria from Chugai, textbook editorial support from Springer, and travel reimbursement from VBL Therapeutics. KMM is a consultant for Tessa Therapeutics and Clovis Oncology. SAG is a consultant for Seattle Genetics; reports receiving research grants from GlaxoSmithKline, Merck, Genentech-Roche, Takeda, Seattle Genetics, Advaxis, Bristol-Meyers Squibb, Abbvie and Tesaro; received travel reimbursement from Intuitive Surgical and Merck; participates in Speakers’ Bureau for Tesaro/GlaxoSmithKline. YGL is an employee of Genentech-Roche; has stock ownership in Genentech-Roche; is a consultant for Venn Biosciences Corporation. RJS is a consultant for Celsion, Incyte, Flatiron Health, Immunogen, and Clovis Oncology. MJB is a consultant for Genentech-Roche, Sanofi, Acceleron Pharma, Merrimack, Oxigene, Threshold Pharmaceuticals, Immunogen, Clovis Oncology, Tesaro, and AstraZeneca.
©2020 American Association for Cancer Research.
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Source: PubMed