Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma.

BACKGROUND: Immune-related adverse events (irAEs) are major barriers of clinical management and further development of immune checkpoint inhibitors (ICIs) for cancer therapy. Therefore, biomarkers associated with the onset of severe irAEs are needed. In this study, we aimed to identify immune features detectable in peripheral blood and associated with the development of severe irAEs that required clinical intervention. METHODS: We used a 43-marker mass cytometry panel to characterize peripheral blood mononuclear cells from 28 unique patients with melanoma across 29 lines of ICI therapy before treatment (baseline), before the onset of irAEs (pre-irAE) and at the peak of irAEs (irAE-max). In the 29 lines of ICI therapy, 18 resulted in severe irAEs and 11 did not. RESULTS: Unsupervised and gated population analysis showed that patients with severe irAEs had a higher frequency of CD4+ naïve T cells and lower frequency of CD16+ natural killer (NK) cells at all time points. Gated population analysis additionally showed that patients with severe irAEs had fewer T cell immunoreceptor with Ig and ITIM domain (TIGIT+) regulatory T cells at baseline and more activated CD38+ CD4+ central memory T cells (TCM) and CD39+ and Human Leukocyte Antigen-DR Isotype (HLA-DR)+ CD8+ TCM at peak of irAEs. The differentiating immune features at baseline were predominantly seen in patients with gastrointestinal and cutaneous irAEs and type 1 diabetes. Higher frequencies of CD4+ naïve T cells and lower frequencies of CD16+ NK cells were also associated with clinical benefit to ICI therapy. CONCLUSIONS: This study demonstrates that high-dimensional immune profiling can reveal novel blood-based immune signatures associated with risk and mechanism of severe irAEs. Development of severe irAEs in melanoma could be the result of reduced immune inhibitory capacity pre-ICI treatment, resulting in more activated TCM cells after treatment.

A single center case series of immune checkpoint inhibitor-induced type 1 diabetes mellitus, patterns of disease onset and long-term clinical outcome.

Background: Type 1 diabetes mellitus (T1DM) is a rare, but serious immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). Our goal was to characterize treatment outcomes associated with ICI-induced T1DM through analysis of clinical, immunological and proteomic data. Methods: This was a single-center case series of patients with solid tumors who received ICIs and subsequently had a new diagnosis of T1DM. ICD codes and C-peptide levels were used to identify patients for chart review to confirm ICI-induced T1DM. Baseline blood specimens were studied for proteomic and immunophenotypic changes. Results: Between 2011 and 2023, 18 of 3744 patients treated at Huntsman Cancer Institute with ICIs were confirmed to have ICI-induced T1DM (0.48%). Eleven of the 18 patients received anti-PD1 monotherapy, 4 received anti-PD1 plus chemotherapy or targeted therapy, and 3 received ipilimumab plus nivolumab. The mean time to onset was 218 days (range 22-418 days). Patients had sudden elevated serum glucose within 2-3 weeks prior to diagnosis. Sixteen (89%) presented with diabetic ketoacidosis. Three of 12 patients had positive T1DM-associated autoantibodies. All patients with T1DM became insulin-dependent through follow-up. At median follow-up of 21.9 months (range 8.4-82.4), no patients in the melanoma group had progressed or died from disease. In the melanoma group, best responses were 2 complete response and 2 partial response while on active treatment; none in the adjuvant group had disease recurrence. Proteomic analysis of baseline blood suggested low inflammatory (IL-6, OSMR) markers and high metabolic (GLO1, DXCR) markers in ICI-induced T1DM cohort. Conclusions: Our case series demonstrates rapid onset and irreversibility of ICI-induced T1DM. Melanoma patients with ICI-induced T1DM display excellent clinical response and survival. Limited proteomic data also suggested a unique proteomic profile. Our study helps clinicians to understand the unique clinical presentation and long-term outcomes of this rare irAE for best clinical management.

Mentorship Initiatives in Radiation Oncology: A Scoping Review of the Literature.

PURPOSE: Although mentorship is described extensively in academic medical literature, there are few descriptions of mentorship specific to radiation oncology. The goal of the current study was to investigate the state of mentorship in radiation oncology through a scoping review of the literature. METHODS AND MATERIALS: A search protocol was defined according to Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for scoping reviews (PRISMA-ScR) guidelines. Predefined search terms and medical subject headings were used to search PubMed for English language articles published after January 1, 1990, on mentorship in radiation oncology. Additionally, in-press articles from major radiation oncology and medical education journals were searched. Three reviewers determined article eligibility. Included articles were classified based on predefined evaluation criteria. RESULTS: Fourteen publications from 2008 to 2019 met inclusion criteria. The most commonly described form of mentorship was the dyad (64.3%), followed by team (14.3%) and peer (7.1%); 2 articles did not specify mentorship type (14.3%). The most commonly mentored participants were residents (35.7%), followed by medical students (35.7%) and attendings (21.4%); 1 study included participants of all levels (7.1%). Thirteen studies (92.9%) identified an experimental study design, most of which were cross-sectional (42.9%), followed by cohort studies (28.6%) and before/after (21.4%). Median sample size, reported in 12 of 13 experimental studies, was 132 (coefficient of variation, 1.06). Although outcomes varied widely, the majority described successful implementation of mentorship initiatives with high levels of participant satisfaction. CONCLUSIONS: Although few initiatives are currently reported, the present study suggests that these initiatives are successful in promoting career development and increasing professional satisfaction. The interventions overwhelmingly described mentorship dyads; other forms of mentorship are either less common or understudied. Limitations included interventions not being evaluated in a controlled setting, and many were assessed using surveys with low response rates. This review highlights rich opportunities for future scholarship to develop, evaluate, and disseminate radiation oncology mentorship initiatives.