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Background: Multiple studies have suggested that gut microbiome may influence immune checkpoint inhibitor (ICI) efficacy, but its association with immune-related adverse events (irAEs) is less well studied. In this prospective cohort study, we assessed whether gut microbiome composition at start, or changes during ICI, are associated with severe irAEs., Methods: Stool samples of cancer patients treated with anti-PD-1 ± anti-CTLA-4 were analyzed using 16S rRNA gene sequencing and metagenomic shotgun sequencing. Differences in alpha and beta diversity between patients with and without severe irAE were assessed, as well as differential relative abundance (RA) of taxa, MetaCyc pathways, and seven prespecified literature-based bacterial groups including pathobionts and Ruminococcaceae., Findings: We analyzed 497 samples of 195 patients before and soon after starting ICI, at severe irAE onset and after starting immunosuppression. Mean RA of the pathobionts group was significantly higher in patients who developed a severe irAE (8.2 %) compared to those who did not (4.8 %; odds ratio 1.40; 95 %CI 1.07-1.87) at baseline, and also early during ICI treatment and at severe irAE onset. A significantly stronger decrease in RA of Ruminococcaceae after starting ICI was observed in patients who developed a severe irAE compared to those who did not. RAs of Ruminococcaceae, the genus Ruminococcus, and the species R. bromii and R. callidus were significantly lower at severe irAE onset compared to other time points., Interpretation: Gut microbiome dysbiosis signaled by higher RA of pathobionts and decrease in RA of Ruminococcaceae may predispose to severe irAEs., Competing Interests: Declaration of Competing Interest FLP is employed at Winclove Probiotics. KPMS reports consulting/advisory relationships with Abbvie, Pierre Fabre, Sairopa. She received honoraria from Bristol Myers Squibb, and research funding from TigaTx, Bristol Myers Squibb, Philips, Pierre Fabre and Genmab. All paid to institution. The other authors declare no conflicts of interest., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs., Methods: Patients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression., Results: Among 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4-8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4-14) and 55 (95 %CI 41-not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HR adj 1.14; 95 %CI 1.01-1.29; HR adj 1.29; 95 %CI 1.12-1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HR adj 1.32; 95 %CI 1.02-1.72) and OS (HR adj 1.34; 95 %CI 0.99-1.82) compared with corticosteroids alone., Conclusions: High corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GAPH reports consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, Merck Sharp and Dome, Pfizer, Novartis, Sanofi, Pierre Fabre and has received research funding from Bristol-Myers Squibb and Seerave. All paid to institution. MJBA reports consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Novartis, Merck Sharp and Dome, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas and Bayer, and received research funding from Merck-Pfizer. All paid to institution. KC reports consultancy fees from Eli Lilly AbbVie and Pfizer. ATJM has received fees from AbbVie, Actelion, CSL Behring, Experf, Novartis, and Shire and declares speaking fees from AstraZeneca, Sanofi-Aventis and Bristol-Myers Squibb. CUB reports consulting/advisory relationships with AstraZeneca, Bristol-Myers Squibb, GenMab, GSK, Lilly, Merck Sharp and Dome, Novartis, Pfizer, Pierre Fabre, Roche and Third Rock Ventures, and received research funding from 4SC, Bristol-Myers Squibb, NanoString and Novartis. All paid to institution. His is co-founder of and owns shares in Immagene BV and Signature Oncology, and is inventor on several related patents (including submitted): WO 2021/177822 A1, N2027907 and P091040NL2. SA reports consulting/advisory relationships with Merck Sharp and Dome, Sanofi, Roche, Bristol-Myers Squibb, Pfizer, Ipsen and Galapagos. All paid to institution. DP reports consultancy/advisory relationships with Pierre Fabre and Novartis. Partly paid to intstitution. EK reports consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Pierre Fabre, Immunocore and Lilly, and received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis and Pierre-Fabre. Not related to current work and paid to institute. ML reports consultancy/advisory relationships with Bristol-Myers Squibb and Janssen-Cilag B.V. All paid to institution. AMMvdV reports consultancy/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Sanofi, Pfizer, Novartis, Roche, Eisai, Merck, Pierre Fabre and Ipsen. All paid to institution. JBAGH reports consultancy/advisory relationships with Achillus Tx, AstraZenica, BioNTech, Bristol-Myers Squibb, CureVac, GlaxoSmithKline, Imcyse, Iovance Bio, Instil Bio, Ipsen, Merck, Merck Sharp and Dome, Molecular Partners, Neogene TX, Novartis, Pfizer, PokeAcell, Roche, Sanofi, Scenic, T-Knife and TRV, and received research funding from Amgen, Bristol-Myers Squibb, BioNTech, Merck Sharp and Dome, Novartis and Sastra Cell Therapy. All paid to institution. KPMS reports consulting/advisory relationships with Bristol-Myers Squibb, Merck Sharp and Dome, Abbvie, Pierre Fabre, Novartis, Sairopa. She received honoraria from Novartis and Merck Sharp and Dome, and research funding from TigaTx, Bristol Myers Squibb, Philips and Genmab. All paid to institution. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Although animal experiments suggest beneficial effects of physical activity (PA) on antitumor immunity, little is known about the effects of PA on immune checkpoint inhibitor (ICI) toxicity and effectiveness in humans. We assessed the association of PA with immune-related adverse events (irAE) and survival in patients undergoing ICI., Methods: Patients receiving ICI who completed the Dutch short questionnaire to assess health enhancing physical activity (SQUASH) questionnaire at the start of treatment as part of the prospective UNICIT study in an academic hospital were included. PA was quantified by calculating total metabolic equivalent task hours per week (total PA) and hours per week of moderate- to vigorous-intensity PA during sport and leisure time (MVPA-SL). Associations of PA with severe irAE occurrence within 1 year and overall survival (OS) were evaluated using logistic regression and Cox proportional hazard regression, respectively, with adjustment for probable confounders., Results: In total, 251 patients were included, with a median follow-up of 20 months. Moderate and high levels of total PA were associated with lower odds of severe irAE occurrence compared to low levels of total PA (adjusted OR: 0.34 [95% CI = 0.12 to 0.90] and 0.19 [95% CI = 0.05 to 0.55], respectively). Moderate and high levels of total PA were also associated with prolonged survival (adjusted HR: 0.58 [95% CI = 0.32 to 1.04] and 0.48 [95% CI = 0.27 to 0.89], respectively). Similar associations were observed in patients who performed more MVPA-SL., Conclusions: Higher physical activity levels at the start of ICI treatment are associated with lower risk of severe irAEs and probably prolonged survival. Randomized controlled trials are needed to investigate whether patients indeed benefit from increasing PA levels after diagnosis., (© The Author(s) 2023. Published by Oxford University Press.)

Colitis is a prevalent adverse event associated with immune checkpoint inhibitor (ICI) therapy with similarities to inflammatory bowel disease. Incomplete mechanistic understanding of ICI colitis curtails evidence-based treatment. Given the often-overlooked connection between tissue architecture and mucosal immune cell function, we here applied imaging mass cytometry (IMC) to gain spatial proteomic insight in ICI colitis in comparison to ulcerative colitis (UC). Using a cell segmentation pipeline that simultaneously utilizes high-resolution nuclear imaging and high-multiplexity IMC, we show that intra-epithelial CD8 + T cells are significantly more abundant (and numerically dominant) in anti-PD-1 ± anti-CTLA-4-induced colitis compared to anti-CTLA-4-induced colitis and UC. We identified activated, cycling CD8 + tissue-resident memory T (RM) cells at the lamina propria-epithelial interface as drivers of cytotoxicity in ICI colitis and UC. Moreover, we found that combined ICI-induced colitis featured highest granzyme B levels both in tissue and serum. Together, these data reinforce CD8 + T RM cells as potentially targetable drivers of ICI colitis., Competing Interests: E.B. received research funding from Pfizer and is supported by the Alexandre Suerman stipend for MD/PhD candidates of the UMC Utrecht. Y.V. has received speaker fees from Johnson & Johnson, research funding from Galapagos, and a Public Private Partnership grant from Health Holland (#TKI2017), with TigaTx B.V. K.S. has advisory relationships with Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, and AbbVie, and received honoraria from Novartis, MSD, and Roche and research funding from BMS, Philips, and TigaTx. All paid to institution. F.W. has received advisory/speaker fees from Takeda and Johnson & Johnson and research funding from BMS, Takeda, Sanofi, Pfizer, Galapagos, and Leo Pharma., (© 2023 The Author(s).)

Changing healthcare requires future physicians to have some basic knowledge of fields related to medicine. There is also a growing need for multidisciplinary and interdisciplinary education in the basic medical curriculum. The basic curriculum is currently being revised on the national level, but this is taking a long time. We are using a practical example to discuss how student-driven education could be a catalyst for rapid change in medical education.