e20647 Background: Immune checkpoint inhibitors (ICIs) are associated with a high risk of immune-related adverse events (irAEs) in pts with TETs (thymoma and thymic carcinoma). PT-112, a novel inducer of immunogenic cell death, has demonstrated safety and efficacy in phase I trials. We present results of an unplanned interim analysis of a phase 2, NIH IRB-approved clinical trial to evaluate the clinical activity, tolerability, and correlative immunology of PT-112 in TETs (NCT05104736). Methods: Eligible pts with TETs with progression after prior platinum therapy were treated with PT-112 360 mg/m2 iv on days 1, 8 and 15 of a 28-day cycle until progression or development of intolerable toxicity. Prior history of autoimmunity (AI) or treatment with ICI was permitted. Primary objective is to determine the objective response rate. Immune activation was assessed by flow cytometry and multiplex immunofluorescence. Results: Ten pts have received treatment (median age 54, 3 females, 5 thymic carcinomas, 3 with prior TET-associated AI disease). Median number of prior systemic therapies is 2.5 (range, 1-4) and all pts have received cisplatin, paclitaxel, or both previously. Nine pts are evaluable for response, with stable disease in 8 (89%) and progressive disease in 1 (11%) pt. After a median potential follow-up of 7.4 months (mo) median progression-free survival is not reached in pts with thymoma and is 6.2 mo (95% CI: 1.8- 7.9 mo) in thymic carcinoma. All pts are evaluable for toxicity. The most common (all grades) treatment-related adverse events (TRAEs) are peripheral neuropathy (60%), anemia, fatigue and myalgias (each in 50%). Grade ≥ 3 TRAEs in more than one patient include anemia (30%) and neutropenia (20%). Two (20%) pts experienced relapse of AI: ocular myasthenia and immune cytopenias. The most common reason for treatment hold is peripheral neuropathy (40%). Treatment was discontinued due to TRAE (peripheral neuropathy) in 1 (10%) pt. There are no treatment related deaths. Treatment was associated with an increase in CD8+ T cells, activated CD4+ T cells and NK cells in peripheral blood. There was an increase in pro-inflammatory serum analytes (IFNg, TNFa, sCD27:sCD40L and sCD73) and a decrease in immunosuppressive analytes (VEGF, sCD40L and TGFb) compared with baseline. Paired tumor biopsies are being analyzed by multiplex immunofluorescence and results will be presented. Conclusions: PT-112 is safe and clinically active in pts with recurrent TETs. In contrast to ICIs, no new irAEs were observed. Immune analyses show evidence of early treatment-related immune activation and support the rationale underlying this novel treatment approach for TETs. Enrollment is ongoing with an accrual ceiling of 53. These initial results support further evaluation of PT-112 in TETs as monotherapy and in combination with other immunomodulatory interventions. Clinical trial information: NCT05104736 .

Circadian variability in kidney function is well recognized but is often ignored as a potential confounding variable in physiological experiments. Here, we have created a data resource consisting of expression levels for mRNA transcripts in microdissected proximal tubule segments from mice as a function of the time of day. Small-sample RNA-sequencing (RNA-seq) was applied to microdissected S1 proximal convoluted tubules (PCTs) and S2 proximal straight tubules (PSTs). After stringent filtering, the data were analyzed using JTK-Cycle to detect periodicity. The dataset is provided as a user-friendly webpage at https://esbl.nhlbi.nih.gov/Databases/Circadian-Prox2/. In PCTs, 234 transcripts varied in a circadian manner (4.0 % of total). In PSTs, 334 transcripts varied in a circadian manner (5.3 %). Transcripts previously known to be associated with corticosteroid action and with increased flow were found to be overrepresented among circadian transcripts peaking during the "dark" portion of the day (Zeitgeber Time [ZT] 14-22), corresponding to the peak levels of corticosterone and glomerular filtration rate in mice. To ask whether there is time-of-day dependence of protein abundances in the kidney, we carried out LC-MS/MS-based proteomics in whole mouse kidneys at ZT12 and ZT0. The full data set (n=6546 proteins) is available at https://esbl.nhlbi.nih.gov/Databases/Circadian-Proteome/. Overall, 293 proteins were differentially expressed between ZT12 and ZT0 (197 greater at ZT12; 96 greater at ZT0). Among the regulated proteins, only 9 had been found to be periodic in the RNA-seq analysis, suggesting a high level of post-transcriptional regulation of protein abundances.