Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFβ) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFβ levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study’s findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity.

Immune-related adverse events (irAEs) are unpredictable autoimmune-like toxicities induced by immune checkpoint inhibitors (ICI). irAEs are a consequence of a breakdown in self-tolerance. ICIs can induce autoantibody formation, and the presence of antinuclear autoantibodies (ANAs) has been reported in patients who developed irAEs. Our goal was to compare ANA patterns by indirect immunofluorescence at different timepoints before (baseline) and after the initiation of ICI treatment and to analyze the role of ANA pattern changes as predictors of irAEs. This is a 2-year-follow-up prospective study of 152 consecutive patients with solid tumors treated with anti-PD-(L)1 blockade agents. They were included from September 2018 until March 2020 in the Hospital de la Santa Creu I Sant Pau (Barcelona, Spain). We grouped patients into three groups: ANA de novo (patients who showed new ANA patterns at any time after ICI initiation), ANA (ANA positive at baseline without changes in the ANA patterns after initiation of treatment) and non-ANA (ANA negative at baseline and after ICI initiation). We did not find any association between the appearance of ANAs and irAE rates or the number and types of irAEs. However, patients in the ANA de novo group showed higher severe irAE rates (grade ≥ 3) than the other groups. Additionally, in most of the patients with severe irAEs (83.3%), changes in ANA patterns preceded irAE onset. In conclusion, we found ANA induction during ICI therapies in 22 patients and our results suggest that the appearance of ANAs may predict the severity of the irAE.

Purpose: CB307 is a trispecific variable heavy-chain antibody fragment against prostate-specific membrane antigen (PSMA), CD137, and human serum albumin. It is designed to mitigate hepatotoxicity by activating T cells only in PSMA-positive tumors and to increase drug half-life through albumin binding. This phase I study investigated the safety and tolerability of CB307 as monotherapy or in combination with pembrolizumab. Patients and Methods: Patients who were heavily pretreated with PSMA-positive solid tumors were enrolled in the dose-escalation phase of CB307 monotherapy. The additional safety and efficacy of CB307 were assessed in the CB307 monotherapy expansion cohort and in combination with pembrolizumab. Results: CB307 was administered to 75 patients. CB307 was given once every 7 days as monotherapy (N = 50) or in combination with pembrolizumab (N = 25). Two dose-limiting toxicities (grade 3 transient transaminitis) were observed. A total of three grade 3 transaminitis events (one in the monotherapy cohort and two in the combination cohort) were observed, and none involved bilirubin elevation. Durable RECIST responses were observed in two patients with metastatic castration-resistant prostate cancer enrolled in the 800 mg CB307 monotherapy and in one patient in the combination cohort (overall response rates: 11.1% and 7.1%, respectively). A disease control rate (DCR) of 50% was observed in patients enrolled in the 800 mg CB307 monotherapy cohort and 42.9% in the combination cohort. In a post hoc analysis, the response was numerically better in patients who had not received chemotherapy in the 6 months prior to starting CB307 (ORR = 20%, DCR = 60% vs. ORR = 0%, DCR = 37.5%). CB307 induces cytotoxic cell expansion in tumors and PD-L1 expression. Conclusions: CB307 was well tolerated as a monotherapy and in combination with pembrolizumab, and tumor responses were observed in patients with metastatic castration-resistant prostate cancer.

Renal cell carcinomas (RCCs) driven by TFE3 rearrangement or TFEB alteration (MiT-RCC) account for up to 40% of pediatric RCCs but are rare in adults. MiT-RCC includes fusion-driven tumors with TFE3 or TFEB rearrangements (translocation RCC, tRCC) and TFEB-amplified RCC. Morphologic heterogeneity and historical exclusion from trials have limited evidence-based management. We reviewed the literature through January 2026 to summarize molecular biology, pathology, clinical behavior, and systemic therapy. MiT-RCC comprises biologically distinct entities: TFEB-rearranged tumors are often indolent in younger patients, whereas TFEB-amplified RCC, frequently co-amplifying VEGFA, behaves aggressively in older adults. In TFE3-rearranged RCC, fusion partner influences prognosis. Paradoxically, ASPSCR1::TFE3 fusions have the poorest natural history, yet fusion-annotated cohorts suggest these tumors may derive particular benefit from immune checkpoint inhibitor (ICI) plus VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI) combinations. Diagnostic advances including GPNMB immunohistochemistry, TRIM63 RNA in situ hybridization, and sequencing-based fusion panels improve detection of cryptic alterations. First-line ICI + VEGFR-TKI combinations are increasingly favored for metastatic tRCC in eligible patients, while optimal management of TFEB-amplified RCC remains uncertain.

Radioligand therapy with [¹⁷⁷Lu]Lutetium-177-PSMA-617 (¹⁷⁷Lu-PSMA) was recently introduced in clinical practice in the US, Latin America and in most European countries for progressive, metastatic castration-resistant prostate cancer (mCRPC). However, multicenter real-world data on cancer-control outcomes are scant. Real-word data from the ARON-3 collaboration in progressive mCRPC patients treated with ¹⁷⁷Lu-PSMA vs. cabazitaxel were collected. A retrospective analysis was performed, including overall survival (OS), progression free survival (PFS), time to treatment failure (TTF) and PSA50/90 rates. Data from 285 (50.1 %) patients receiving ¹⁷⁷Lu-PSMA vs. 283 (49.9 %) cabazitaxel after one or two lines of ARPI and Docetaxel were analyzed. PSA50 and PSA90 rates were higher, and TTF and OS were significantly longer in ¹⁷⁷Lu-PSMA patients, even after multivariable adjustment (p ≤ 0.01). This effect held true for most subgroups such as age < 70 and ≥ 70 years, ECOG 0-1, distant lymph nodes and one vs. two lines of prior ARPI. Incidence of grade 3-4 adverse events were comparable between both treatments (37 % vs. 43 % for ¹⁷⁷Lu-PSMA vs. cabazitaxel cohort p = 0.5) but differed according to the type of adverse events. Sensitivity analyses with cross-over adjustment showed similar effects. Analyzing the currently largest real-world cohort comparing ¹⁷⁷Lu-PSMA vs. cabazitaxel, we provided robust information of ¹⁷⁷Lu-PSMA being at least equally effective or possibly even superior to cabazitaxel regarding cancer-control outcomes with reasonable side effects.