Radiation therapy (RT) in some cases results in a systemic anticancer response known as the abscopal effect. Multiple hypotheses support the role of immune activation initiated by RT-induced DNA da... Lay abstract Radiation therapy works by damaging DNA, which causes cells to die. Typically, radiation therapy is used to directly affect cancer cell growth at the directed site. However, reports of...

Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors, many such cases are preventable with vaccination against high-risk serotypes of the human papilloma virus (HPV 6, 11, 16, 18, 31, 33, 45, 53, 58). Advanced-stage and recurrent cervical cancers are typically lethal and have been the focus in recent years of the integration of immune checkpoint inhibitors (CPIs) to improve survival. We have consolidated information regarding the role of the immune system in both disease progression and disease clearance with the aid of targeted therapies and immunotherapeutic agents. Additionally, we have characterized the treatment modalities currently indicated as the standard of care—such as bevacizumab and the immune CPIs—and those recently approved or in development, including Tivdak, Vigil, and chimeric antigen receptor (CAR) T-cells.

Resident memory T (T_RM) cells are a unique subset of CD8⁺ T cells that are present within certain tissues and do not recirculate through the blood. Long term memory establishment and maintenance are dependent on tissue population of memory T cells. They are characterized by dual CD69/CD103 positivity, and play a role in both response to viral infection and local cancer immunosurveillance. Human T_RM cells demonstrate the increased expression of adhesion molecules to facilitate tissue retention, have reduced proliferation and produce both regulatory and immune responsive cytokines. T_RM cell phenotype is often characterized by a distinct expression profile driven by Runx3, Blimp1, and Hobit transcription factors. The accumulation of T_RM cells in tumors is associated with increased survival and response to immunotherapies, including anti-PD-1 and anti-CTLA-4. In this review, we explore potential mechanisms of T_RM cell transformation and maintenance, as well as potential applications for the use of T_RM cells in both the development of supportive therapies and establishing more accurate prognoses.

The primary objective of the FDA-led Sequencing and Quality Control Phase 2 (SEQC2) project is to develop standard analysis protocols and quality control metrics for use in DNA testing to enhance scientific research and precision medicine. This study reports a targeted next-generation sequencing (NGS) method that will enable more accurate detection of actionable mutations in circulating tumor DNA (ctDNA) clinical specimens. To accomplish this, a synthetic internal standard spike-in was designed for each actionable mutation target, suitable for use in NGS following hybrid capture enrichment and unique molecular index (UMI) or non-UMI library preparation. When mixed with contrived ctDNA reference samples, internal standards enabled calculation of technical error rate, limit of blank, and limit of detection for each variant at each nucleotide position in each sample. True-positive mutations with variant allele fraction too low for detection by current practice were detected with this method, thereby increasing sensitivity.

Background: Standardized Nucleic Acid Quantification for SEQuencing (SNAQ-SEQ) is a novel method that utilizes synthetic DNA internal standards spiked into each sample prior to next generation sequencing (NGS) library preparation. This method was applied to analysis of normal appearing airway epithelial cells (AEC) obtained by bronchoscopy in an effort to define a somatic mutation field effect associated with lung cancer risk. There is a need for biomarkers that reliably detect those at highest lung cancer risk, thereby enabling more effective screening by annual low dose CT. The purpose of this study was to test the hypothesis that lung cancer risk is characterized by increased prevalence of low variant allele frequency (VAF) somatic mutations in lung cancer driver genes in AEC.Methods: Synthetic DNA internal standards (IS) were prepared for 11 lung cancer driver genes and mixed with each AEC genomic (g) DNA specimen prior to competitive multiplex PCR amplicon NGS library preparation. A custom Perl script was developed to separate IS reads and respective specimen gDNA reads from each target into separate files for parallel variant frequency analysis. This approach identified nucleotide-specific sequencing error and enabled reliable detection of specimen mutations with VAF as low as 5 × 10^− 4(0.05%). This method was applied in a retrospective case-control study of AEC specimens collected by bronchoscopic brush biopsy from the normal airways of 19 subjects, including eleven lung cancer cases and eight non-cancer controls, and the association of lung cancer risk with AEC driver gene mutations was tested.Results: TP53 mutations with 0.05–1.0% VAF were more prevalent (p < 0.05) and also enriched for tobacco smoke and age-associated mutation signatures in normal AEC from lung cancer cases compared to non-cancer controls matched for smoking and age. Further, PIK3CA and BRAF mutations in this VAF range were identified in AEC from cases but not controls.Conclusions: Application of SNAQ-SEQ to measure mutations in the 0.05–1.0% VAF range enabled identification of an AEC somatic mutation field of injury associated with lung cancer risk. A biomarker comprising TP53, PIK3CA, and BRAF somatic mutations may better stratify individuals for optimal lung cancer screening and prevention outcomes.

Acknowledging the correlation of response to therapy based on the “targeting the target” concept, FDA demonstrated confidence in precision therapy approaches by approving Foundation One® CDx test in late 2017 as an indicated diagnostic for cancer patients. More than 100 precision therapies involving both solid and liquid malignancy have since been approved by FDA as indicated therapy in a variety of cancer types as related to correlated molecular target. We provide clinical justification of consideration for precision therapy guided by matched molecular target, specifically focusing on PI3K/mTOR/AKT, BRCA, CDK4/6, EGFR and BRAF V600E for advanced disease cancer patients who previously failed optimal NCCN guideline directed standard of care.