1176 Anti-RANKL bone resorptive therapy increases immune related adverse events (irAEs) during checkpoint inhibitor therapy
Year: 2024
Type: conference-abstract
Abstract: Background Immune related adverse events (irAEs) occur in up to 60–70% of patients treated with immune checkpoint inhibitor [ICI, e.g. anti-programmed death protein (anti-PD1)] cancer therapy1 and present as autoimmune disease in healthy tissues, including endocrine, gastrointestinal, skin, lung, liver, and the nervous system. Such irAEs can cause rapid autoimmune destruction of healthy organs and contribute to hospitalizations (8–25% of patients), cancer therapy discontinuation (64% of patients), and premature death (5.6% of patients).2 How adjunctive treatments during cancer care, such as bone protective anti-resorptive therapies, affect the rate of irAEs is largely unknown. In particular, anti-RANKL therapies were recently shown to improve ICI anti-tumor efficacy in some cancer types, including melanoma3 and non-small cell lung cancer.4 Methods Our study evaluated the effect of combined anti-RANKL treatment with anti-PD1 therapy on the incidence of irAEs in a cohort of breast cancer patients and in a mouse model of irAEs. Results In a cohort of ICI-naïve adult patients with early and advanced breast cancer treated with anti-PD1 therapy at an academic cancer center, we found that patients with prior or concurrent treatment with anti-RANKL (denosumab) had an increased rate of severe (Grade 3+) irAEs compared to patients who received anti-PD1 therapy alone [12/56 (21.4%) versus 40/345 (11.6%)]. To better understand the role of anti-RANKL therapy in vivo, we then turned to our recently established mouse model of irAEs in which autoimmunity-prone, non-obese diabetic (NOD) mice treated with ICI therapy develop autoimmune infiltrates in multiple organs, including thyroiditis and accelerated autoimmune diabetes. Indeed, pre-treatment with one week of anti-RANKL therapy significantly increased the rate of endocrine irAEs in our mice during anti-PD1 therapy. Anti-RANKL therapy was also associated with a trend toward decreased T regulatory cells in ICI-treated mice and has previously been shown to affect thymic negative selection of T cells, including Treg development, through modulation of medullary thymic epithelial cell (mTEC) antigen expression.5 Conclusions Taken together, these data highlight a new risk factor for irAEs with anti-RANKL therapy. 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Ethics Approval The study obtained ethics approval (IRB 22403) and the participants gave informed consent before taking part.
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4404065270