Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

Reliability of the Functional Independence Measure with Occupational Therapists

This paper reports an inter-rater reliability study on the Functional Independence Measure (FIM). The FIM measures inpatient burden of care, as reflected in 18 self care items, rated on a seven point scale from dependent to independent. The subjects were 40 occupational therapists, divided according to experience with the FIM and randomly assigned to a FIM training or non-training group. Subjects rated video tapes of four stroke patients on transfers, bathing, dressing, grooming, toileting and eating items from the FIM. Rater consensus was calculated using the intraclass correlation coefficient (ICC), percentage agreement and a measure of disagreement. Rating accuracy was measured by comparisons with an expert rater. Ratings were most reliable when done by clinicians with no prior FIM experience, from the FIM training group. It is strongly recommended that all clinicians undergo FIM training before using this tool to ensure acceptable reliability.