Charalampos S. Floudas

Somatostatin receptor 2 is expressed in nasopharyngeal carcinoma (NPC). We report genomic and transcriptomic analysis results of 163 NPC cases, demonstrating that somatostatin receptor 2 ( SSTR2 ) gene expression in EBV‐positive and in EBV‐negative NPC correlated with genomic alterations and an inflamed microenvironment. Median SSTR2 expression was 6.52 transcripts per million (TPM), ranging from 0.59 TPM (Quartile 1 [Q1], 18.2% EBV‐positive) to 35.79 TPM (Q4, 82.9% EBV‐positive). PIK3CA (20.51%) and CYLD (10.53%)/ NFKBIA (12.82%) mutations were enriched in SSTR2 ‐Q1 versus ‐Q4. Tumor mutation burden was negatively correlated ( R = −0.27, p < 0.001) with SSTR2 , while PD‐L1 tumor proportion score (2% vs. 92.5% [ SSTR2 :Q1 vs. Q4], p < 0.001) and T‐cell inflamed score correlated with SSTR2 expression ( R = 0.53, p < 0.001). B‐cells, M1 macrophages, CD8+ T‐cells, Treg cells, and dendritic cells were enriched in SSTR2 ‐Q4, while neutrophils were prominent in SSTR2 ‐Q1. These results demonstrate a significant positive correlation between SSTR2 expression and an inflamed tumor microenvironment in NPC. This suggests that SSTR2 expression in NPC may be a clinically useful biomarker, correlating with the tumor microenvironment (including, potentially, sensitivity to immunotherapy) and its genetic profile.

Background: There is no established treatment for patients with recurrent/metastatic (R/M) olfactory neuroblastoma (ONB), a rare sinonasal tumor. We conducted the first immunotherapy clinical trial (NCT05012098) in patients with R/M ONB, to evaluate the activity of the bifunctional TGF-β “trap”/anti-PD-L1 fusion protein bintrafusp alfa (BA). Methods: Patients received BA (1200 mg, intravenously) every 2 weeks. Primary endpoint was overall response rate (ORR); secondary objectives included safety, progression-free survival (PFS), and overall survival (OS). Results: Between June 2022 and June 2023, 11 patients received treatment (Cohort 1, no prior immunotherapy, n=9; Cohort 2, prior immunotherapy received, n=2); enrollment was stopped due to BA development discontinuation. No objective responses were observed. In Cohort 1, 4 patients (of 8 evaluable, 50%) had stable disease (SD), three confirmed and long lasting; median PFS was 3.7 months, median OS was not reached; and one of SD patients had a complete metabolic response on ⁶⁸ Ga-DOTATATE imaging. In Cohort 2, 1 patient had SD; median PFS was 3 months, and median OS was 6.8 months. Grade 3/4 treatment-related adverse events occurred in 3 patients (immune-mediated diabetes, esophageal hemorrhage, anemia, epistaxis). Conclusions: Although the primary endpoint was not met, BA showed a manageable safety profile and a subset of patients derived clinical benefit with prolonged stable disease, including one patient with a complete metabolic response. This first clinical trial of systemic therapy in R/M ONB serves as proof of clinical trials feasibility in this setting and supports further investigation of combinatorial immunotherapy strategies in this patient population. Trial registration ClinicalTrials.gov Identifier: NCT05012098, https://clinicaltrials.gov/ct2/show/NCT05012098 . Registered 18 August 2021.

Oropharyngeal squamous cell carcinomas (OPSCCs) frequently result from oncogenic human papilloma virus (HPV) infections (HPV-OPSCC). The mechanisms underlying effective immune escape, despite abundant viral antigens, are incompletely understood. Here, we performed single-cell spatial gene expression profiling of HPV-OPSCC to characterize cellular organization and mechanisms of immune resistance. We describe distinct tumor-parenchymal immune foci that differ in cytokine expression, spatial location, immune cell infiltration and cancer cell states. Furthermore, immune foci display profound differences related to co-inhibitory receptor signaling and immunosuppressive myeloid cells, suggesting that different tumor-parenchymal regions may be dominated by distinct, locally-confined mechanisms of immunosuppression. Additionally, senescent-like HPV-OPSCC cells lacking HPV transcripts (HPVoff) are evident across the tumor parenchyma and able to evade HPV-specific T cell-mediated immunity in vitro. HPVoff cells are enriched within hypoxic regions and near IFN-γ producing T cells suggesting that both hypoxia and IFN-γ signaling can promote the HPVoff phenotype. In conclusion, our findings highlight a complex cellular interplay underlying heterogeneous cancer cell states, spatial immune cell organization, and diverse mechanisms of immune escape.

Despite the reduced impact of COVID-19 due to widespread vaccination and improved treatments, a critical need remains for accessible, scalable, and rapid screening tools to address current and future infectious disease threats. Hyperspectral Imaging (HSI) may be such a tool, but the current limited availability of data from COVID-19 positive individuals hinders traditional supervised learning approaches. To overcome this, we designed a novel framework that integrates HSI with Artificial Intelligence (AI) analysis for detecting COVID-19 status from images of fingertips, thereby demonstrating infection detection through biometric data. By analyzing high-dimensional spectral signatures from the fingertip, the approach identifies distinctive patterns linked to physiological changes caused by the virus. In this pilot study, a Support Vector Machine (SVM) and a Logistic Regression classification algorithm demonstrated high accuracy in classifying HSI images, underscoring the potential of hyperspectral features for non-invasive, real-time health monitoring, even with the limitations of a small dataset. We introduced the first publicly available dataset of HSI images from COVID-19-positive individuals. This contribution sets a foundation for advancing biometric spectral imaging in biomedical research and AI-powered diagnostics. The datasets used during this study is available from the corresponding author upon reasonable request.

Background: Early termination, defined as the discontinuation of a trial before its planned completion, remains poorly characterized in phase 1 cancer trials. We aimed to (1) identify reasons for early termination in phase 1 trials and compare them with those in late-phase studies and (2) investigate temporal patterns and factors associated with early termination in phase 1 trials. Methods: Trials on solid tumors initiated between 2018 and 2023 were identified using the Aggregate Analysis of ClinicalTrials.gov database. We compared the reasons for early termination between phase 1 and phase 2 to 3 trials using the χ2 test. We estimated the cumulative probability of early termination over time and used a multivariable logistic regression model to investigate determinants of early termination. Results: We included 2301 studies: 1740 phase 1 and 561 phase 2 to 3 trials. “Sponsor/strategic decisions” was the most common reason for early termination in phase 1 trials (51.1%), while “poor accrual” predominated in phase 2 to 3 trials (35.5%; P < .001). The probability of early termination in phase 1 trials increased rapidly between 10 and 30 months after initiation and plateaued after 60 months. Factors associated with a lower probability of early termination included academic funding and conduct in Europe, Asia, or Oceania. Conversely, trials conducted globally or enrolling patients with thoracic or gastrointestinal cancers were more likely to be discontinued prematurely. Conclusions: Phase 1 trials are primarily discontinued for “sponsor/strategic decisions.” Funding source, tumor type, and geographic location of recruiting centers are independently associated with early termination. The early peak in early termination probability marks a critical window for interventions to improve trial sustainability.

Background: Despite successes in other malignancies, immune checkpoint blockade (ICB) has not demonstrated reproducible efficacy in mismatch repair-proficient (pMMR) colorectal cancer (CRC). Preclinical studies indicate that multitargeted combination immunotherapy may sensitize resistant tumors to immune-mediated killing. This trial was designed to test this hypothesis by combining agents to induce and augment an immune response in pMMR CRC. Methods: In this single-center, phase 1/2 trial, eligible patients had pMMR, RECIST v1.1-measurable metastatic CRC, ≥2 prior lines of therapy, and no prior immunotherapy. The primary endpoint was objective response rate. Patients received triplet therapy: CV-301 (CEA/MUC-1 vaccine), N-803 (IL-15 receptor superagonist), bintrafusp alfa (bifunctional anti-PD-L1/TGFβ “trap”), or quadruplet therapy (adding PDS01ADC [tumor-targeted IL-12 immunocytokine]). Results: Between September 2020 and September 2022, 32 patients enrolled in triplet (n = 12) and quadruplet (n = 20) therapy. The combinations had toxicity profiles consistent with each individual agent included. One complete response durable for 29+ months occurred in a patient with RAS wild-type CRC metastatic to lymph nodes who received quadruplet therapy. Conclusion: Quadruplet therapy produced one objective response in unselected mCRC patients (n = 20). There were no responses with triplet therapy (n = 12). The role of ICB-based combination immunotherapy in pMMR CRC remains unclear. NCT04491955