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

Abstract

Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune‐related adverse events (irAEs). Immunosuppression with high dose corticosteroids, or tumor necrosis factor (TNF) antagonists in refractory cases, is the mainstay of treatment for irAEs. It is currently unknown what impact corticosteroids and anti‐TNF have on the activity of antitumor T cells. In our study, the influence of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10–125 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 doses impaired the activation (−46 and −62%, respectively) and tumor‐killing ability (−48 and −53%, respectively) 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 72‐hr resting period 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. In conclusion, clinically relevant doses of infliximab only had a minor influence on the activity of tumor‐specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. However, the activity of TILs could be restored after withdrawal of steroids. These data indirectly support steroid‐sparing strategies and early initiation of anti‐TNF therapy for the treatment of irAEs in immuno‐oncology.

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 …”

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors

“…77 However, recent preclinical data point out that glucocorticoids markedly impair the activation and the killing ability of tumour-infiltrating lymphocytes. 161 Because of concerns of glucocorticoids on antitumour responses, the task force did not recommend using methylprednisolone pulses or high-dose oral glucocorticoids in the absence of life-threatening complications and myositis, even in severe presentations, and favoured the concept of glucocorticoid sparing where rheumatologists have extensive experience with alternative options. Furthermore, the task force members recommended tapering glucocorticoids to the lowest effective dose within weeks or as soon as improvement is achieved was desirable.…”

“…The objective of reaching a dose less than or equal to 10 mg/day of equivalent prednisone was considered as an acceptable target dose. This target dose as maintenance therapy is based on current preclinical and retrospective clinical data, [161][162][163] and higher than the one recommended for the main classical RMDs (online supplementary table S2). In case of active rheumatic irAE requiring dose of glucocorticoids higher than 10 mg/day of equivalent prednisone, conventional synthetic disease-modifying antirheumatic drug (csDMARD) should be considered.…”

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

“…The irAEs, i.g. colitis, are managed by corticosteroid administration (270,271), but refractory cases are treated with infliximab once ICB is suspended. Considering the aforementioned mechanisms of TNFα-induced ICB resistance, preclinical studies investigated the prophylactic effect of TNFα blockade both to impede irAEs development and to enhance ICB's efficacy.…”