Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer.

Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as "viral mimicry," has emerged as an effective strategy to convert immunologically "cold" tumors into "hot." Through a curated CRISPR-based screen of RNA helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers (SCLC). Depletion of DHX9 induced accumulation of cytoplasmic dsRNA and triggered tumor-intrinsic innate immunity. Intriguingly, ablating DHX9 also induced aberrant accumulation of R-loops, which resulted in an increase of DNA damage-derived cytoplasmic DNA and replication stress in SCLCs. In vivo, DHX9 deletion promoted a decrease in tumor growth while inducing a more immunogenic tumor microenvironment, invigorating responsiveness to immune-checkpoint blockade. These findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, representing a promising target for SCLC and other "cold" tumors in which genomic instability contributes to pathology. SIGNIFICANCE: One promising strategy to trigger an immune response within tumors and enhance immunotherapy efficacy is by inducing endogenous "virus-mimetic" nucleic acid accumulation. Here, we identify DHX9 as a viral-mimicry-inducing factor involved in the suppression of double-stranded RNAs and R-loops and propose DHX9 as a novel target to enhance antitumor immunity. See related commentary by Chiappinelli, p. 389. This article is featured in Selected Articles from This Issue, p. 384.

How to Treat EGFR-Mutated Non-Small Cell Lung Cancer.

•Mutations in the EGFR gene are observed in about 15% of NSCLC adenocarcinomas in the United States and are not associated with smoking. There are numerous EGFR mutations, with the most common being exon 19 deletions and the point mutation L858R in exon 21.•Osimertinib, an oral TKI, is used as the initial therapy for metastatic NSCLC harboring exon 19 deletion and exon 21 L858R mutation. Common side effects include acneiform rash, diarrhea, and paronychia. Osimertinib has also been associated with cardiomyopathy (∼1.4%-2.4%) and prolongation of the QT interval (2.7%).•In our experience, osimertinib-induced cardiomyopathy can be managed with the cessation of osimertinib and the initiation of guideline-directed therapy. Given that osimertinib is often the best available therapy, rechallenging with osimertinib often favors benefit over risk. Safe rechallenge with osimertinib is demonstrated in this case.

Predictors of Pneumonitis in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation Followed by Consolidative Durvalumab.

Purpose: In patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), the standard of care is concurrent chemoradiation (CRT) followed by consolidative immunotherapy with durvalumab. Pneumonitis is a known adverse event of both radiation therapy and immune checkpoint inhibitors such as durvalumab. We sought to characterize pneumonitis rates and dosimetric predictors of pneumonitis in a real-world population of patients with NSCLC treated with definitive CRT followed by consolidative durvalumab. Methods and Materials: Patients with NSCLC from a single institution who were treated with definitive CRT followed by consolidative durvalumab were identified. Outcomes of interest included pneumonitis incidence, type of pneumonitis, progression-free survival, and overall survival. Results: Sixty-two patients were included in our data set treated from 2018 to 2021 with a median follow-up of 17 months. The rate of grade 2+ pneumonitis in our cohort was 32.3%, and the rate of grade 3+ pneumonitis was 9.7%. Lung dosimetry parameters including V20 ≥30% and mean lung dose (MLD) >18 Gy were found to be correlated with increased rates of grade 2+ and grade 3+ pneumonitis. Patients with a lung V20 ≥30% had a grade 2+ pneumonitis rate at 1 year of 49.8% compared with 17.8% in patients with a lung V20 <30% (P = .015). Similarly, patients with an MLD >18 Gy had a grade 2+ pneumonitis rate at 1 year of 52.4% compared with 25.8% in patients with an MLD ≤18 Gy (P = .01). Moreover, heart dosimetry parameters including mean heart dose ≥10 Gy were found to be correlated with increased rates of grade 2+ pneumonitis. The estimated 1-year overall survival and progression-free survival of our cohort were 86.8% and 64.1%, respectively. Conclusions: The modern management of locally advanced, unresectable NSCLC involves definitive chemoradiation followed by consolidative durvalumab. Pneumonitis rates were higher than expected in this cohort, particularly for patients with a lung V20 ≥30%, MLD >18 Gy, and mean heart dose ≥10 Gy, suggesting that more stringent radiation planning dose constraints may be needed.

Emerging Biomarkers in Immune Oncology to Guide Lung Cancer Management.

Over the last decade, the use of targeted therapies and immune therapies led to drastic changes in the management lung cancer and translated to improved survival outcomes. This growing arsenal of therapies available for the management of non-small cell lung cancer added more complexity to treatment decisions. The genomic profiling of tumors and the molecular characterization of the tumor microenvironment gradually became essential steps in exploring and identifying markers that can enhance patient selection to facilitate treatment personalization and narrow down therapy options. The advent of innovative diagnostic platforms, such as next-generation sequencing and plasma genotyping (also known as liquid biopsies), has aided in this quest. Currently, programmed cell death ligand 1 expression remains the most recognized and fully validated predictive biomarker of response to immune checkpoint inhibitors. Other markers such as tumor mutational burden, tumor infiltrating lymphocytes, driver mutations, and other molecular elements of the tumor microenvironment bear the potential to be predictive tools; however, the majority are still investigational. In this review, we describe the advances noted thus far on currently validated as well as novel emerging biomarkers that have the potential to guide the use of immunotherapy agents in the management of non-small cell lung cancer.

Use of antibiotics is associated with worse clinical outcomes in patients with cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

OBJECTIVES: Observational and experimental studies suggest that the use of antibiotics close to administration of immune checkpoint inhibitors (ICI) can have a negative effect on tumour response and patient survival, due to microbiome dysbiosis and the resultant suppression of host immune response against neoplastic cells. METHODS: A systematic search of PUBMED and EMBASE was undertaken for studies published between 1 January 2017 and 1 June 2020, evaluating the association between the use of antibiotics and clinical outcomes in patients with cancer treated with ICIs. A meta-analysis of the association between the use of antibiotics and clinical outcomes was also performed. RESULTS: Forty-eight studies met the inclusion criteria (12,794 patients). Use of antibiotics was associated with shorter overall survival [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.59-2.22; adjusted HR 1.87, 95% CI 1.55-2.25] and progression-free survival (HR 1.52, 95% CI 1.36-1.70; adjusted HR 1.93, 95% CI 1.59-2.36), decreased response rate [odds ratio (OR) 0.54, 95% CI 0.34-0.86] and more disease progression (OR 2.00, 95% CI 1.27-3.14). The negative association between the use of antibiotics and progression-free survival was stronger in patients with renal cell carcinoma or melanoma compared with lung cancer. Only antibiotic administration >1 month prior to ICI initiation was associated with increased disease progression. Heterogeneity was substantial for all outcomes. CONCLUSIONS: Recent use of antibiotics in patients with cancer treated with ICIs was associated with worse clinical outcomes. Such patients may benefit from dedicated antimicrobial stewardship programmes.

Non-Bacterial Thrombotic Endocarditis as a Cause of Cryptogenic Stroke in Malignancy.

Non-bacterial thrombotic endocarditis (NBTE) is characterized by the deposition of fibrin and platelet thrombi on previously undamaged heart valves in the absence of bloodstream infection. It is associated with chronic disease states and can present with systemic embolic disease. Here we report a case of NBTE presenting as recurrent strokes in a patient with bladder cancer. Importantly, transthoracic echocardiography has limitations to detecting valvular lesions in NBTE, and providers should consider obtaining transesophageal echocardiography in the setting of high clinical suspicion.