Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses: Implications for the management of irAEs
Authors: A. Draghi, T.H. Borch, H.D. Radic, C. Chamberlain, A. Gokuldass, I.-M. Svane, M. Donia
Journal: Annals of Oncology (2018)

Background: Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune-related adverse events (irAEs). Immunosuppression with high doses of corticosteroids or, in refractory cases, with tumor necrosis factor (TNF) antagonists, are the mainstay of treatment for irAEs. It is currently unknown what is the impact of corticosteroids and anti-TNF on the activity of tumor-specific T cells. Methods: The influence of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10 to 125 mg oral prednisolone) and infliximab (anti-TNF, corresponding to the steady-state concentration for the infusion dose of 5mg/kg) on the activation and killing capacity of tumor-infiltrating lymphocytes (TILs) or tumor-specific peripheral blood lymphocytes (PBLs) was tested in vitro. The activation of lymphocytes following recognition of autologous tumor cells (percentage of CD8+ T cells staining positive for the activation marker 4-1BB/CD137) was evaluated with flow cytometry at different time points. The tumor-specific killing ability of TILs versus autologous tumor cells was evaluated in the impedance-based xCELLigence system. Results: Overall, dexamethasone at low or intermediate/high doses impaired the activation (respectively -46% and -62% in n = 8) and tumor-killing ability (respectively -48% and -53% in n = 6) of TILs. However, even high doses of dexamethasone did not abrogate TILs activity. In contrast, a standard clinical dose of infliximab only had a minor effect on the activation and tumor-killing ability of TILs (respectively -20% in n = 8 and -10% in n = 6). Similar results were obtained comparing the activation of tumor-specific CD8+ PBLs. A 72-hour resting after withdrawal of dexamethasone was sufficient to rescue the in vitro activity of TILs, while a short withdrawal did not result in a full rescue. Conclusions: Clinically-relevant doses of infliximab only influenced to a lesser extent the activity of tumor-specific T cells in vitro, whereas even low doses of corticosteroids markedly impaired their antitumor functions. These data indirectly support steroid-sparing strategies and early initiation of anti-TNF for the treatment of irAEs in immuno-oncology. Legal entity responsible for the study: Herlev and Gentofte Hospital. Funding: These works were supported by a research grant to Inge Marie Svane from The Danish Cancer Society, Knæk Cancer campaign. Disclosure: T.H. Borch: Honoraria for lectures: Bristol-Myers Squibb; Financial support for attending symposia: Bristol-Myers Squibb, Roche. I-M. Svane: Honoraria for lectures: Novartis, Roche, Merck, Bristol-Myers Squibb; Research grant: Novartis; Financial support for attending symposia: Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche. M. Donia: Honoraria for lectures: Bristol-Myers Squibb, Merck, AstraZeneca, Genzyme; Financial support for attending symposia: Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche. All other authors have declared no conflicts of interest.