Issues
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Cover Image
Cover Image
Cancers within the pleural cavity such as malignant pleural mesothelioma (MPM) are aggressive and typically have poor response to therapies. Immune checkpoint inhibitors have been indicated for second-line use in this disease; however, low expression of PD-L1 has contributed to poor response in patients given monotherapy. Chimeric antigen receptor (CAR) T cells developed to target mesothelin and be delivered to the pleural cavity have shown promise in mouse models, but PD-1/PD-L1 signaling promoted functional exhaustion of these CAR T cells; administration of an anti–PD-1 therapy abrogated this effect. Adusumilli and colleagues therefore conducted a first-in-human phase I clinical trial combining pembrolizumab with intrapleural administration of CAR T cells targeting mesothelin. This trial indicated that this combination was not only feasible and safe but had antitumor efficacy, with two patients with MPM experiencing complete metabolic responses, and persistence of functional CAR T cells was observed. For more information, see the article by Adusumilli and colleagues on page 2748. - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
Mini Review
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Research Briefs
MET Amplification Attenuates Lung Tumor Response to Immunotherapy by Inhibiting STING
Efficacy, Safety, and Biomarker Analysis of Combined PD-L1 (Atezolizumab) and VEGF (Bevacizumab) Blockade in Advanced Malignant Peritoneal Mesothelioma
Research Articles
A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti–PD-1 Agent Pembrolizumab
The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets
The multinational pediatric precision oncology INFORM registry identified subgroups of patients benefiting with improved progression free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.
Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative
DNA and RNA sequencing of paired primary tumor/metastases from 381 patients with metastatic breast cancer shed light on enriched genomic alterations, subtype switching, and immune cell composition, and identified new candidate biomarkers of premature lethality.
Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial
Prostate cancers that benefit most from PARP inhibition have BRCA2 alterations, with BRCA2 homozygous loss associating with the longest benefit; biallelic loss of PALB2 and ATM can also sensitize to PARP inhibition.
Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional STK11 Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown
Enhancer Hijacking Drives Oncogenic BCL11B Expression in Lineage-Ambiguous Stem Cell Leukemia
Selective Requirement of MYB for Oncogenic Hyperactivation of a Translocated Enhancer in Leukemia
Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma
Surface IL1RAP maintains cyst(e)ine and glutathione pools to block anoikis and facilitate metastatic dissemination in Ewing sarcoma, and minimal expression in normal tissues nominates IL1RAP as a promising immunotherapy target.
Medium-Chain Acyl-CoA Dehydrogenase Protects Mitochondria from Lipid Peroxidation in Glioblastoma
Genetic screening revealed a novel function for MCAD in glioblastoma, where in addition to its energetic role, it prevents toxic lipid accumulation, and targeting MCAD causes irreversible damage and cell death in glioblastoma cells, while sparing normal cells.
AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia
Leukemia cells evade immune control by engaging the AXL receptor tyrosine kinase in innate immune cells; targeting AXL lifts the innate immune barriers, triggers lymphocyte-mediated leukemic clearance, and elicits response to adaptive checkpoint therapy.
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