Significance: Ebola virus (EBOV) infection is a severe, often fatal disease with poorly understood pathophysiology. Here, we performed [ ¹⁸ F]-DPA-714 Positron Emission Tomography (PET) in a macaque model of EBOV infection to longitudinally track and quantify the translocator protein (TSPO), an immune cell marker. The imaging findings, along with immunohistology and other disease markers, showed increasing stem cell proliferation in the bone marrow, along with progressive monocytic and lymphocytic loss in the spleen and lungs. This study provides real-time noninvasive assessment of EBOV pathogenesis and disease progression, as well as the associated host responses, at the organ level. This approach can be similarly used to study other inflammatory and infectious diseases and to test the efficacy of newly developed therapeutics and vaccines.

Polycomb repressive complex 2 (PRC2) is known to regulate gene expression and chromatin structure as it methylates H3K27, resulting in gene silencing. Studies have shown that PRC2 has dual functions in oncogenesis that allow it to function as both an oncogene and a tumor suppressor. Because of this, nuanced strategies are necessary to promote or inhibit PRC2 activity therapeutically. Given the therapeutic vulnerabilities and associated risks in oncological applications, a structured literature review on PRC2 was conducted to showcase similar cofactor competitor inhibitors of PRC2. Key inhibitors such as Tazemetostat, GSK126, Valemetostat, and UNC1999 have shown promise for clinical use within various studies. Tazemetostat and GSK126 are both highly selective for wild-type and lymphoma-associated EZH2 mutants. Valemetostat and UNC1999 have shown promise as orally bioavailable and SAM-competitive inhibitors of both EZH1 and EZH2, giving them greater efficacy against potential drug resistance. The development of other PRC2 inhibitors, particularly inhibitors targeting the EED or SUZ12 subunit, is also being explored with the development of drugs like EED 226. This review aims to bridge gaps in the current literature and provide a unified perspective on promising PRC2 inhibitors as therapeutic agents in the treatment of lymphomas and solid tumors.

Background: Immune checkpoint inhibitor (ICI)-associated acute interstitial nephritis (AIN) is a recognized complication of immunotherapy (IO), but literature on its management and outcomes is limited. Methods: We retrospectively reviewed patients who received ICIs and developed biopsy-proven or clinically-suspected ICI-associated AIN at the University of Virginia Comprehensive Cancer Center from 2012–2023. We analyzed baseline characteristics and clinical outcomes, including treatment interruption and rechallenge rates. Acute kidney injury (AKI) was defined as a ≥ 1.5-fold increase in baseline creatinine under seven days, a two-fold increase above the upper limit of normal, or an increase by ≥0.3 mg/dL. Kidney function returning to within 0.3 mg/dL or less than twice baseline was considered complete (CRc) and partial (PRc) recovery, respectively. Results: We identified 12 cases of ICI-AIN: four by biopsy (33%) and eight (67%) by clinical suspicion. Two patients received anti-CTLA-4 and anti-PD1, six received anti-PD1 alone, and four received chemo-immunotherapy. The majority (58%) of patients developed AIN within the first 5 cycles. Eight patients developed ≥ Grade 3 AKI, and six developed multiple irAEs. ICI was permanently discontinued in seven patients (58%) and temporarily interrupted in four (30%). The CRc and PRc rates were 67% and 8%, respectively. Upon AIN onset, the best disease response was stable disease in five patients, partial response in three, and progressive disease in three. Median overall survival was 4.87 years, and progression-free survival was 1.5 years. Conclusions: Rechallenge with IO after kidney irAE may be possible in some patients but requires careful evaluation on an individual basis.

Background: Mucosal melanoma (MM) is a rare and aggressive subtype of melanoma with a notably worse prognosis than cutaneous melanoma (CM) due to its occult presentation and unique molecular profile. For advanced cases, immunotherapy has improved outcomes in recent years, although more significantly for CM. The recently approved combination of nivolumab and relatlimab has emerged as a promising option for advanced melanoma and a potential alternative to the well‐established nivolumab‐ipilimumab regimen. Due to the rarity of MM often limiting thorough evaluation in trials, there remains a lack of guidance regarding the most appropriate regimen for optimal patient outcomes. Case: A 70‐year‐old male with T4aN0M0 sinonasal MM was initiated on neoadjuvant nivolumab‐ipilimumab therapy; however, disease progression soon after rendered the tumor unresectable. Despite undergoing 4 cycles, metastatic progression ensued, necessitating a shift to nivolumab‐relatlimab therapy. Following 8 cycles of nivolumab‐relatlimab alongside radiation to metastatic sites, the patient achieved a complete response, with no signs of active disease. Unfortunately, during a seven‐week treatment interruption due to suspected immune‐related gastrointestinal toxicity requiring corticosteroids, routine PET‐CT monitoring revealed findings suspicious for new metastasis. Despite one additional cycle of immunotherapy, the patient's functional status deteriorated. Although repeat imaging showed stable disease, the patient elected to transition to supportive care without further treatment. Conclusion: This case exemplifies the use of nivolumab‐relatlimab in achieving a complete response in a patient with advanced sinonasal MM that progressed after nivolumab‐ipilimumab. While further investigation is needed to clarify the comparative efficacy of existing combination immunotherapy options, this report highlights nivolumab‐relatlimab as a promising option with a potentially favorable safety profile in this rare and aggressive melanoma subtype.

Objective: Immune checkpoint inhibitors (ICIs) are widely utilized in treating various malignancies but are associated with immune-related adverse events (irAEs), which often poses challenges to their use. Pancreatic irAEs, though rare, can present as new-onset diabetes, pancreatitis, or asymptomatic lipase elevation, often altering the clinical trajectory and quality of life of patients. This study sought to expand the understanding of this rare toxicity by summarizing the characteristics and outcomes of low-grade and high-grade pancreatic irAEs. Methods: We conducted a single-center, retrospective study of adult patients treated with checkpoint inhibitors between 2010 and 2022. Patients with clinical or radiographic evidence of pancreatic injury associated with ICI therapy were included. Pancreatic irAEs were defined as low-grade (< grade 3) or high-grade (≥ grade 3) using the Common Terminology Criteria for Adverse Events. Results: Of 21 patients identified with pancreatic irAEs, 76% (n = 16) experienced high-grade severity, often requiring hospitalization. The majority of patients presented with either new-onset diabetes (n = 11) or pancreatitis (n = 11). Most low-grade irAEs resolved, while the majority of high-grade events did not, particularly due to the lasting nature of insulin-dependent diabetes. ICI rechallenge was attempted in most cases, although conclusions regarding subsequent disease and survival outcomes are limited. Conclusions: Pancreatic irAEs, though uncommon, often present at higher toxicity grades at onset and require substantial medical intervention, whether acutely in the hospital or longitudinally in the outpatient setting. Early identification and management remain critical, and ICI rechallenge appears to be feasible in select patients. Further research is required to better predict and manage severe pancreatic irAEs.