Pre-existing autoimmune disease as a risk factor for immune-related adverse events in cancer patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have been widely used as standard therapies for various cancers. However, in 20-30% of cases, ICIs can lead to immune-related adverse events (irAEs), which sometimes require discontinuation of treatment. Due to the increased risk of irAEs, patients with pre-existing autoimmune diseases (AI) are often advised against receiving ICIs. However, there has not been sufficient objective risk assessment for AI. In our study, we conducted logistic regression analysis to assess the risk of irAEs by analyzing 478 cases that received anti-PD-(L)1 Ab and/or anti-CTLA4 Ab at our hospital between April 3, 2017, and May 24, 2022. Among these cases, 28 (5.9%) had pre-existing AI. We selected several independent factors for analysis: gender, age, performance status (PS), cancer type, type of ICI, type of combined anti-cancer agents, best overall response, and pre-existing AI. The adjusted odds ratio (OR) of AI for irAE occurrence was 2.52 [95% CI: 1.08-5.86] (p = 0.033), and the adjusted OR of AI for ICI discontinuation due to irAE was 3.32 [1.41-7.78] (p = 0.006). Patients with pre-existing AI experienced a significantly shorter irAE-free survival time compared to those without AI (median irAE-free survival: 5.7 months [95% CI: 3.5-7.8] vs 10.4 months [95% CI: 7.9-12.9], respectively, p = 0.035). Frequently observed irAEs in full ICI cohort, such as dermatologic issues (7.5%), pneumonitis (7.1%), hepatitis (4.6%), and hypothyroidism (4.2%), were often accompanied by pre-existing AI. Furthermore, pre-existing AI flared up in 6 cases (37.5% in AI-positive irAE-positive cases). The activity of AI was not related to the occurrence of irAEs. Grade 3 or higher irAEs were observed in 6 out of 20 (30.0%) cases in AI-accompanied patients complicated with irAEs. Although having a complicated AI increases the risk of irAEs, it may not necessarily be a contraindication for ICI treatment if closely monitored. (292<300 characters).

Augmentation of the cytotoxic effects of nitrogen-containing bisphosphonates in hypoxia.

OBJECTIVES: Tumour hypoxia is a major obstacle in cancer therapy that leads to poor prognosis. Therefore, the development of cancer treatments that are effective in hypoxia is necessary. Nitrogen-containing bisphosphonates (N-BPs), which are used to treat bone disease, are cytotoxic to several cancer cells in normoxia. Therefore, we investigated the cytotoxicity of N-BPs in cancer cells in hypoxia. METHODS: We studied the cytotoxicities of N-BPs, statins and anticancer drugs in human cancer cells under hypoxic conditions (1% O2 ). The expression levels of enzymes in the mevalonate pathway in hypoxia were measured by real-time reverse transcription polymerase chain reaction and Western blotting. KEY FINDINGS: In hypoxia, cell growth inhibition by 5-fluorouracil and cisplatin was not changed as compared to that in normoxia; however, cell growth inhibition by N-BPs and via zoledronate-induced apoptosis was higher in hypoxia than that in normoxia. Furthermore, geranylgeraniol completely inhibited the growth inhibitory effects of zoledronate. Additionally, the mRNA and protein levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase significantly decreased in hypoxia. Moreover, simvastatin potentiated the growth inhibitory effect of zoledronate. CONCLUSIONS: The cytotoxicity of N-BPs, but not 5-fluorouracil and cisplatin, is potentiated in hypoxia, through the loss of HMG-CoA reductase function. N-BPs may be effective against cancer in normoxia and hypoxia.