Citations

Abstract Immune checkpoint inhibitors (ICIs) have limited benefit in recurrent high-grade astrocytoma (rHGA), largely because the blood–brain barrier and a profoundly immunosuppressive tumor microenvironment prevent T cells from infiltrating. Laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive procedure that can “heat up” these otherwise “cold” tumors and sensitize them to ICIs. In this tri-institutional Phase 1/randomized Phase 2 trial (NCT02311582), bevacizumab- and immunotherapy-naïve rHGA patients were initially randomized 1:1 to either LITT followed by pembrolizumab (LITT+PEM) or non-LITT surgery (biopsy or resection) followed by pembrolizumab (NLS+PEM). Phase 2 participants enrolled at a second recurrence—with several already at a third recurrence—underscoring the advanced disease stage of this cohort. After 21 patients, randomization was halted when contemporaneous evidence showed limited benefit from adjuvant ICIs alone, and the remaining 24 patients received only LITT+PEM. In the 21-patient intent-to-treat cohort, LITT+PEM extended median OS to 21.3 months with 54% alive at 18 months (OS18) versus 6.7 months with 12.5% OS18 with NLS+PEM (HR 0.29; 95% CI, 0.01–0.88; p=0.021). Median PFS was 7.8 versus 2.2 months (HR 0.3; 95% CI, 0.10–0.87; p=0.020). Among 39 per-protocol patients, LITT+PEM yielded a median OS of 11.8 months with 42% OS18 versus 5.2 months with 0% OS18 for NLS+PEM (HR 0.17; 95% CI, 0.06–0.49; p=0.0002), and a median PFS of 4.5 versus 1.6 months (HR 0.21; 95% CI, 0.08–0.56; p=0.0006). The combination was well tolerated. Immune profiling revealed that LITT triggers early activation of non-classical monocytes—a change associated with improved survival—while subsequent pembrolizumab unleashes robust CD8⁺ T cell proliferation and clonal expansion. Long-term LITT+PEM survivors developed coordinated memory T-cell responses, whereas shorter-surviving patients exhibited stagnant memory pools and exhausted phenotypes. Together, these results demonstrate that LITT plus pembrolizumab is safe, overcomes rHGA’s immunosuppressive barrier, and mobilizes robust anti-tumor immunity.

Abstract Glioblastoma (GBM), the most aggressive primary brain tumor in adults, is marked by profound immune suppression. Tumor-derived extracellular vesicles (TEVs) are increasingly recognized as key mediators of this immunosuppressive environment. In this study, we examined the tumor-immune microenvironment using ultrasonic aspirate samples from GBM patients (n = 14). Several immune checkpoint molecules, including PDL1, B7-H3, and VISTA, were notably elevated. TIGIT, a receptor typically associated with T cells, was widely expressed across multiple myeloid subsets, including monocytic myeloid-derived suppressor cells (mMDSCs; 64.27 ± 7.99%) and non-classical monocytes (NCM; 39.8 ± 4.37%). Co-culture of healthy donor monocytes (n=10) with TEVs replicated similar effects (control 11.69±1.87 vs EV treated 23.32±2.0). We found CD155, the primary TIGIT ligand, to be heavily enriched in TEVs and co-expressed with TIGIT in co-culture, suggesting the TIGIT/CD155 axis may be involved in promoting immune suppression. Additionally, induced MDSCs significantly inhibit T cell proliferation (30.65±5.97% proliferation, v/s control 86.47±2.94, p=0.0001), concomitant with a surge in Th2 immune responses via TIGIT+ monocytes along with an increase in NLRP3 and IL-1β expressing cells. Interestingly, TIGIT knockdown did not affect NLRP3 expression but did restore T cell proliferation (64.13 ± 1.33%; p = 0.02) and pro-inflammatory cytokine production. However, the restoration of T cell proliferation was lost when NLRP3 was also silenced, indicating its essential role in mediating immune rescue. Overall, our findings highlight a crucial role of TIGIT in driving myeloid-mediated immune suppression in GBM. Furthermore, TIGIT inhibition may unmask NLRP3 function, potentially contributing to immune rescue.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive disease caused by the deposition of transthyretin (TTR) as amyloid in the myocardium. Current therapies may slow disease progression but do not clear existing deposits. Coramitug is a humanized monoclonal antibody that targets misfolded transthyretin, designed to promote clearance of transthyretin amyloid through antibody-mediated phagocytosis. METHODS: This phase 2, double-blind, placebo-controlled trial randomized participants with transthyretin amyloidosis with cardiomyopathy to receive infusions every 4 weeks of either coramitug at 2 dosages (10 mg/kg or 60 mg/kg) or placebo in a 1:1:1 ratio for 52 weeks. The primary end points were the change from baseline to week 52 in the 6-minute walk test and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Safety was assessed for up to 64 weeks by assessing treatment-emergent adverse events, all-cause mortality, and number of cardiovascular events (comprising hospitalization caused by cardiovascular events or urgent heart failure visits). RESULTS: In total, 104 participants (median age, 77 years; 93% men; 84% New York Heart Association class II; 13% with variant transthyretin amyloidosis with cardiomyopathy) were randomized and dosed: 34 to 10 mg/kg of coramitug, 35 to 60 mg/kg of coramitug, and 35 to placebo. Median NT-proBNP was 1985 pg/mL (interquartile range, 1224, 3406). In total, 90% of participants were receiving disease-modifying therapy; 84% were treated with tafamidis and 7 (6.7%) with transthyretin silencers (patisiran, n=4; vutrisiran, n=3). From baseline to week 52, 60 mg/kg of coramitug significantly reduced NT-proBNP levels compared with placebo (–48% [95% CI, –65% to –22%]; P =0.0017). The change in 6-minute walk test from baseline to week 52 was not statistically different from placebo with either dose. Coramitug (60 mg/kg) was associated with improved functional echocardiographic parameters and was well tolerated. CONCLUSIONS: This phase 2 trial showed that coramitug, an antibody targeting misfolded transthyretin in transthyretin amyloidosis with cardiomyopathy, was well tolerated and, at a dose of 60 mg/kg, resulted in a statistically significant reduction in NT-proBNP, a validated marker of disease progression, with no statistically significant effect on 6-minute walk test within 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05442047.

Obstructive sleep disordered breathing (oSDB), including obstructive sleep apnea (OSA), frequently coexists with cleft lip and palate, velopharyngeal insufficiency (VPI), and other craniofacial conditions. Moreover, oSDB is often a key factor in decisions for primary or revision cleft palate or velpharyngeal surgery. Due to the frequency with which cleft and craniofacial team members care for patients with oSDB, this article provides a primer for OSA evaluation and management for team members. oSDB can have a significant impact on quality of life, health outcomes, surgical planning, and global development for all children, especially those with cleft and craniofacial conditions. In this review, oSDB screening and testing methods are discussed, including interpretation of OSA testing. Considerations for specific craniofacial populations are included, such as those with 22q11.2 deletion syndrome and Pierre-Robin sequence. The impact of VPI surgery on OSA is discussed. Finally, approaches to OSA management are reviewed, with attention to how standard management approaches may shift in children with cleft and craniofacial conditions. As awareness of oSDB in children has increased, including increased access to diagnostic testing, studies have shown certain patient populations are more likely to have OSA and would benefit from screening. Children with craniofacial conditions, including cleft palate and velopharyngeal insufficiency, have altered risk profiles which impact management considerations for OSA. This article provides an introduction to key concepts in oSDB screening, diagnositics, and management, which can be valuable for any professional assisting in the care of children with a cleft or craniofacial condition.

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.