Phase I Trial of Cemiplimab, Radiotherapy, Cyclophosphamide, and Granulocyte Macrophage Colony-Stimulating Factor in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

Lessons Learned: Cemiplimab in combination with radiation therapy, cyclophosphamide, and granulocyte macrophage colony-stimulating factor did not demonstrate efficacy above what can be achieved with other PD-1 inhibitor monotherapies in patients with refractory and metastatic head and neck squamous cell carcinoma. The safety profile of cemiplimab combination therapy was consistent with previously reported safety profiles of cemiplimab monotherapy. No new safety signal was observed.

PD-1 blockade in recurrent or metastatic cervical cancer: Data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer.

Objectives: To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression.

Methods: In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort).

First-In-Human Study of Cemiplimab Alone or In Combination with Radiotherapy and/or Low-dose Cyclophosphamide in Patients with Advanced Malignancies.

Purpose: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors.

Patients And Methods: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m) CPA.

Genetic analysis of albuminuria in collaborative cross and multiple mouse intercross populations.

Albuminuria is an important marker of nephropathy that increases the risk of progressive renal and chronic cardiovascular diseases. The genetic basis of kidney disease is well-established in humans and rodent models, but the causal genes remain to be identified. We applied several genetic strategies to map and refine genetic loci affecting albuminuria in mice and translated the findings to human kidney disease.

Genome-wide association mapping of quantitative traits in outbred mice.

Recent developments in high-density genotyping and statistical analysis methods that have enabled genome-wide association studies in humans can also be applied to outbred mouse populations. Increased recombination in outbred populations is expected to provide greater mapping resolution than traditional inbred line crosses, improving prospects for identifying the causal genes. We carried out genome-wide association mapping by using 288 mice from a commercially available outbred stock; NMRI mice were genotyped with a high-density single-nucleotide polymorphism array to map loci influencing high-density lipoprotein cholesterol, systolic blood pressure, triglyceride levels, glucose, and urinary albumin-to-creatinine ratios.

Non-invasive blood pressure measurement in mice.

Hypertension is a leading cause of heart attack, stroke, and kidney failure and represents a serious medical issue worldwide. The genetic basis of hypertension is well-established, but few causal genes have been identified thus far. Non-invasive blood pressure measurements are a critical component of high-throughput genetic studies to identify genes controlling blood pressure.

Genetic analysis of blood pressure in 8 mouse intercross populations.

The genetic basis of hypertension is well established, yet very few genes that cause common forms of hypertension are known. Quantitative trait locus (QTL) analyses in rodent models can guide the search for human hypertension genes, but the excellent genetic resources for mice have been underused in this regard. To address this issue, we surveyed blood pressure variation in mice from 37 inbred strains and generated 2577 mice in 8 intercross populations to perform QTL analyses of blood pressure.

Validation of volume-pressure recording tail-cuff blood pressure measurements.

Background: The American Heart Association has recommended tail-cuff blood pressure measurement for high-throughput experimental designs, including mutagenesis screens and genetic crosses. However, some tail-cuff methods show good agreement with radiotelemetry and others do not, indicating that each tail-cuff method requires independent validation.

Methods: We validated the volume-pressure recording (VPR) tail-cuff method by comparison to simultaneous radiotelemetry measurements.