Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses - implications for the management of irAEs

Abstract

Abbreviations: CTCAE Common Terminology Criteria for Adverse Events ICI Immune checkpoint inhibitors irAE Immune-related adverse event PBL Peripheral blood lymphocyte PBMC Peripheral blood mononuclear cell REP Rapid expansion TIL Tumor-infiltrating lymphocyte TNF Tumor necrosis factor 2 Abstract: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 antitumor T cells. In this study, the influences of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10 to 125 mg prednisolone) and infliximab (anti-TNF) on the activation and killing ability of tumor-infiltrating lymphocytes (TILs) was tested in vitro. Overall, dexamethasone at low or intermediate/high dose impaired the activation (respectively -46% and -62%) and tumor-killing ability (respectively -48% and -53%) of tumor-specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T cell activation (-20%) and tumor killing (-10%). A brief resting following exposure to dexamethasone was sufficient to rescue the in vitro activity of TILs. In conclusion, clinically-relevant doses of infliximab only influenced to a lesser extent the activity of tumor-specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. These data support steroid-sparing strategies and early initiation of anti-TNF for the treatment of irAEs in immuno-oncology.

Tumors induce de novo steroid biosynthesis in T cells to evade immunity

“…The study adds to the concern raised by recent studies about proper use of steroids, particularly glucocorticoids, in solid tumors as a part of the disease management, specifically when we seek to boost anti-tumor immune response [55][56][57][58][59][60][61][62] . Glucocorticoids have been used in clinical oncology for over a half a century, and at present these are routinely used to alleviate edema in patients with intracranial lesions and are first-line agents to suppress immune-related adverse events that arise with the immunotherapies.…”

Colitis after checkpoint blockade: A retrospective cohort study of melanoma patients requiring admission for symptom control

“…On the other hand, prior in vitro and animal experiments have shown that glucocorticoids block antibody‐dependent tumor cell destruction; may abrogate interleukin‐1α‐mediated antitumor activity; and upregulate CTLA‐4 in animal models of intracranial gliomas responsive to CTLA‐4 inhibition . A recent study concluded in addition that infliximab, in contrast to corticosteroids, had little to no negative impact on tumor‐infiltrating lymphocyte function …”

Immune-related adverse events associated with immune checkpoint inhibitors in patients with cancer

“…Studies show that the use of additional immunosuppressive agents such as anti-TNF-α and the administration of systemic corticosteroids for irAEs do not diminish the survival benefits of immunotherapeutic agents. 16 In a retrospective study of 298 patients with melanoma treated with ipilimumab, one-third of patients received systemic corticosteroid therapy and 10% received anti-TNF-α for irAEs. There was no difference in survival between the patients who received corticosteroids or anti-TNF-α drugs and those who did not.…”