PRGN-2012 gene therapy in adults with recurrent respiratory papillomatosis: a pivotal phase 1/2 clinical trial.

Background: Recurrent respiratory papillomatosis (RRP) is a rare debilitating condition caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Papillomas develop in the aerodigestive tract, leading to significant voice disturbance and airway obstruction. No systemic treatment currently exists.

Characterization of Somatostatin Receptor 2 Gene Expression and Immune Landscape in Sinonasal Malignancies.

Olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC), and sinonasal neuroendocrine carcinoma (SNEC) are rare malignancies arising from the sinonasal tract with limited therapeutic options. The expression of the somatostatin receptor 2 gene (), which is expressed in other neuroendocrine neoplasms and is therapeutically actionable, has been reported in these tumors. Here, we analyzed gene expression and its associations with genomic features, established biomarkers predicting of immune response, and the tumor immune microenvironment in a cohort of ONB, SNUC, and SNEC tumor samples (26, 13, and 8 samples, respectively) from a real-world database.

Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variants.

Background: Adoptive T-cell therapy has demonstrated clinical activity in B-cell malignancies, offering hope for its application to a broad spectrum of cancers. However, a significant portion of patients with solid tumors experience primary or secondary resistance to this treatment modality. Target antigen loss resulting either from non-uniform antigen expression or defects in antigen processing and presentation machinery is one well-characterized resistance mechanism.

The effects of moderate alcohol and THC co-use during male and female rat adolescence on AKT-GSK3ß signaling in adulthood.

Alcohol and cannabis are often taken in combination, and extensive co-use has been linked to enduring changes in cognitive and metabolic functioning. The underlying mechanisms for these effects are unclear, but we recently demonstrated that co-administration of ethanol and delta-9-tetrahydrocannbinol (THC) to adolescent rats caused lasting adaptations in GABA and glycogen synthase kinase 3ß (GSK3ß) signaling in the medial prefrontal cortex (mPFC). As a ubiquitous protein kinase, GSK3ß is downstream to the protein kinase B (also known as AKT) pathway that is activated by insulin receptor signaling in a main control center for metabolism and energy homeostasis, the mediobasal hypothalamus (MBH).

Stimulating Soluble Guanylyl Cyclase with the Clinical Agonist Riociguat Restrains the Development and Progression of Castration-Resistant Prostate Cancer.

Castration-resistant prostate cancer (CRPC) is incurable and fatal, making prostate cancer the second leading cancer-related cause of death for American men. CRPC results from therapeutic resistance to standard-of-care androgen deprivation (AD) treatments, through incompletely understood molecular mechanisms, and lacks durable therapeutic options. In this study, we identified enhanced soluble guanylyl cyclase (sGC) signaling as a mechanism that restrains CRPC initiation and growth.

Efficacy and safety of bintrafusp alfa in 2 phase I expansion cohorts with advanced HCC.

Background And Aims: Simultaneous inhibition of the TGF-β and programmed cell death 1 ligand 1 pathways provides a potential novel treatment approach. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death 1 ligand 1, was evaluated in patients with advanced HCC.

Approach And Results: In this global, open-label, phase I study (NCT02517398), patients with programmed cell death 1 ligand 1-unselected HCC who failed or were intolerant to ≥1 line of sorafenib received bintrafusp alfa 1200 mg every 2 weeks in a dose-escalation (n = 38) or dose-expansion (n = 68) cohort until confirmed progression, unacceptable toxicity, or trial withdrawal.

TGF-β neutralization attenuates tumor residency of activated T cells to enhance systemic immunity in mice.

A tissue resident-like phenotype in tumor infiltrating T cells can limit systemic anti-tumor immunity. Enhanced systemic anti-tumor immunity is observed in head and neck cancer patients after neoadjuvant PD-L1 immune checkpoint blockade (ICB) and transforming growth factor β (TGF-β) neutralization. Using T cell receptor (TCR) sequencing and functional immunity assays in a syngeneic model of oral cancer, we dissect the relative contribution of these treatments to enhanced systemic immunity.

Hepatic artery infusion pump (HAIP) therapy in combination with targeted delivery of IL-12 for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma: a phase II trial protocol.

Background: Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed.

Hypothesis: the generation of T cells directed against neoepitopes employing immune-mediating agents other than neoepitope vaccines.

The development of vaccines, especially RNA-based, directed against patient-specific tumor neoepitopes is an active and productive area of cancer immunotherapy. Promising clinical results in melanoma and other solid tumor types are emerging. As with all cancer therapy modalities, neoepitope vaccine development and delivery also has some drawbacks, including the level of effort to develop a patient-specific product, accuracy of algorithms to predict neoepitopes, and with the exception of melanoma and some other tumor types, biopsies of metastatic lesions of solid tumors are often not available.

A deep-learning framework to predict cancer treatment response from histopathology images through imputed transcriptomics.

Advances in artificial intelligence have paved the way for leveraging hematoxylin and eosin-stained tumor slides for precision oncology. We present ENLIGHT-DeepPT, an indirect two-step approach consisting of (1) DeepPT, a deep-learning framework that predicts genome-wide tumor mRNA expression from slides, and (2) ENLIGHT, which predicts response to targeted and immune therapies from the inferred expression values. We show that DeepPT successfully predicts transcriptomics in all 16 The Cancer Genome Atlas cohorts tested and generalizes well to two independent datasets.

Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors.

Purpose: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts.

Methods: This is an investigator-initiated, multicenter, phase I trial.

Challenges and opportunities in cancer immunotherapy: a Society for Immunotherapy of Cancer (SITC) strategic vision.

Cancer immunotherapy has flourished over the last 10-15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge.

Augmentation of tumor expression of HLA-DR, CXCL9, and CXCL10 may improve olfactory neuroblastoma immunotherapeutic responses.

Background: Olfactory neuroblastoma is a rare malignancy of the anterior skull base typically treated with surgery and adjuvant radiation. Although outcomes are fair for low-grade disease, patients with high-grade, recurrent, or metastatic disease oftentimes respond poorly to standard treatment methods. We hypothesized that an in-depth evaluation of the olfactory neuroblastoma tumor immune microenvironment would identify mechanisms of immune evasion in high-grade olfactory neuroblastoma as well as rational targetable mechanisms for future translational immunotherapeutic approaches.

Utility of Large Language Models for Health Care Professionals and Patients in Navigating Hematopoietic Stem Cell Transplantation: Comparison of the Performance of ChatGPT-3.5, ChatGPT-4, and Bard.

Background: Artificial intelligence is increasingly being applied to many workflows. Large language models (LLMs) are publicly accessible platforms trained to understand, interact with, and produce human-readable text; their ability to deliver relevant and reliable information is also of particular interest for the health care providers and the patients. Hematopoietic stem cell transplantation (HSCT) is a complex medical field requiring extensive knowledge, background, and training to practice successfully and can be challenging for the nonspecialist audience to comprehend.

Chordoma cancer stem cell subpopulation characterization may guide targeted immunotherapy approaches to reduce disease recurrence.

Introduction: Cancer stem cells (CSCs), a group of tumor-initiating and tumor-maintaining cells, may be major players in the treatment resistance and recurrence distinctive of chordoma. Characterizing CSCs is crucial to better targeting this subpopulation.

Methods: Using flow cytometry, six chordoma cell lines were evaluated for CSC composition.

Deep learning-based whole-body PSMA PET/CT attenuation correction utilizing Pix-2-Pix GAN.

Purpose: Sequential PET/CT studies oncology patients can undergo during their treatment follow-up course is limited by radiation dosage. We propose an artificial intelligence (AI) tool to produce attenuation-corrected PET (AC-PET) images from non-attenuation-corrected PET (NAC-PET) images to reduce need for low-dose CT scans.

Methods: A deep learning algorithm based on 2D Pix-2-Pix generative adversarial network (GAN) architecture was developed from paired AC-PET and NAC-PET images.

Using Photovoice to Improve Engagement in Community Health Assessments Addressing Behavioral Health.

Behavioral health disorders are well-known to have close links with the social determinants of health, yet little is known about how impacted communities perceive these links. Qualitative participatory methods can not only provide insight into how communities conceptualize these relationships but also empower those with lived experience to contextualize their perspectives and formulate calls to action. This study used Photovoice as a participatory method to supplement the Clark County Health Department Community Health Assessment and determine priority facilitators and barriers contributing to the behavioral health of Clark County, KY, residents.

States' investment in recovery support services: An exploratory analysis.

Introduction: Recovery support services (RSS), while not yet precisely defined, nevertheless have a longstanding role in managing chronic illnesses including substance use disorders (SUDs). This exploratory study is the first to identify the amounts of money that states invest from Substance Abuse and Mental Health Services Administration (SAMHSA) Block Grants; SAMHSA discretionary grant and state-appropriated sources; the types of organizations from which RSS are purchased; and the non-financial supports states provide for RSS.

Methods: The study is a mixed method exploratory analysis, based on three data sources: content analysis of all 51 (Washington, D.

Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced non-small cell lung cancer.

Background: Bintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell lung cancer (NSCLC) in a dose expansion cohort of the phase 1, open-label clinical trial (NCT02517398). Here, we report the safety, efficacy, and biomarker analysis of bintrafusp alfa in a second expansion cohort of the same trial (biomarker cohort).

Methods: Patients with stage IIIb/IV NSCLC who were either immune checkpoint inhibitor (ICI)-naïve (n=18) or ICI-experienced (n=23) were enrolled.

The role of sex and drug use during adolescence in determining the risk for adverse consequences of amphetamines.

Use of amphetamines during adolescence, a critical period of brain development and reorganization, may lead to particularly adverse outcomes that are long-lasting. Similarly, female users may be uniquely vulnerable to certain aspects of drug use. A recognition of the role of use during adolescence and sex on outcomes of amphetamine and methamphetamine exposure are of critical importance in understanding and treating substance use disorders.

Timing of methamphetamine exposure during adolescence differentially influences parvalbumin and perineuronal net immunoreactivity in the medial prefrontal cortex of female, but not male, rats.

Adolescence involves significant reorganization within the medial prefrontal cortex (mPFC), including modifications to inhibitory neurotransmission mediated through parvalbumin (PV) interneurons and their surrounding perineuronal nets (PNNs). These developmental changes, which result in increased PV neuron activity in adulthood, may be disrupted by drug use resulting in lasting changes in mPFC function and behavior. Methamphetamine (METH), which is a readily available drug used by some adolescents, increases PV neuron activity and could influence the activity-dependent maturational process of these neurons.

Increasing diversity in clinical trials: demographic trends at the National Cancer Institute, 2005-2020.

Background: We described participant demographics for National Cancer Institute (NCI) clinical trials at the clinical center (NCI-CC participants) of the National Institutes of Health to identify enrollment disparities.

Methods: We analyzed NCI-CC data from 2005 to 2020, calculated enrollment fractions, compared with the US cancer population represented by the Surveillance, Epidemiology, and End Results cancer incidence data (2018) and the Cancer in North America database (2018), and compared further with clinical trial disparities data from the NCI Community Oncology Research Program and National Clinical Trials Network (2005-2019), and from ClinicalTrials.gov (2003-2016).