Journal
ANNALS OF ONCOLOGY
Volume 26, Issue 10, Pages 2141-2149Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdv309
Keywords
ovarian cancer; interleukin-6; immunotherapy; chemoresistance; tumor immunity
Categories
Funding
- Bontius Foundation
- Department of Medical Oncology of the Leiden University Medical Center
- Dutch Cancer Society [2009-4400]
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Background: The immune system is important in epithelial ovarian cancer (EOC). Interleukin-6 is associated with chemoresistance and an immune-suppressive tumor microenvironment. We investigated whether a combination of chemotherapeutics, blockade of interleukin 6 (IL-6) receptor (IL-6R; tocilizumab), and immune enhancer interferon-alpha (Peg-Intron) is feasible, safe, and able to enhance immunity in patients with recurrent EOC. Patients and methods: In this dose-escalation study, patients received tocilizumab 1, 2, 4, or 8 mg/kg i.v., q4 weeks during the first three cycles of carboplatin (AUC5) plus doxorubicin [pegylated liposomal doxorubicin (PLD) 30 mg/m(2) or doxorubicin 50 mg/m(2) i.v., day 1, q4 weeks, for six cycles]. At the highest tocilizumab dose (8 mg/kg), Peg-Intron (1 mu g/kg s.c.) was added. Peripheral blood mononuclear cells were collected for immunomonitoring at baseline, after three and six cycles. Dose-limiting toxicity (DLT), CA-125, and radiologic response were evaluated. Results: In the 23 patients enrolled, no DLT was established. The most frequent grade 3/4 adverse events (CTCAE v4.03) were neutropenia (23%), febrile neutropenia (19%), and ileus (19%). No treatment-related deaths occurred. Using CT evaluation, 11 of 21 assessable patients responded, 6 had stable disease and 3 progressive disease. Patients receiving highest dose tocilizumab showed a functional blockade of IL-6R with increased levels of serum IL-6 (P = 0.02) and soluble IL-6R (P = 0.008). Consequently, immune cells displayed decreased levels of pSTAT3, myeloid cells produced more IL-12 and IL-1 beta while T cells were more activated and secreted higher amounts of effector cytokines interferon-gamma and tumor necrosis factor-alpha. An increase in sIL-6R was potentially associated with a survival benefit (P = 0.03). Conclusions: Functional IL-6R blocking is feasible and safe in EOC patients treated with carboplatin/(pegylated liposomal) doxorubicin, using 8 mg/kg tocilizumab. This combination is recommended for phase II evaluation based on immune parameters.
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