Blood
Glucarpidase for Treatment of High-Dose Methotrexate Toxicity
Gupta S, Kaunfer SA, Chen KL, Dias JA, Patel A, Ni J, Krishnamurthy S, Ali R, Yilmam OA, Wells SL, Ortega JL, Green-Lingren OL, Leaf RK, Sise ME, Nayak L, LaCasce AS, Leaf DE
High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine <1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69-4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18-3.33) and lower risks of grade ?2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28-0.91) and grade ?2 transaminitis (aOR, 0.50; 95% CI, 0.28-0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49-1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.
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Cancer Discovery
Response and Resistance to RAS Inhibition in Cancer
Ebright RY, Dilly J, Shaw AT, Aguirre AJ
RAS inhibitors have shown early evidence of efficacy in multiple cancer types, but clinical benefit is limited by acquired resistance. Development of best-in-class inhibitors, with optimal potency, selectivity, and pharmacokinetic properties, as well as effective and tolerable combination therapies will be needed to overcome resistance and maximize the clinical impact of RAS-targeted therapy.
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Cancer Discovery
The Future of Personalized Cancer Vaccines
Martini DJ, Wu CJ
In early clinical studies, genomics-guided personalized cancer vaccines (PCVs) have demonstrated the capabilities of inducing long-term, tumor-specific immune responses across various malignancies, clinical settings, and treatment regimens. Now that PCVs have advanced to large-scale, randomized clinical trials, we are at a pivotal time. The future success of PCVs will likely be dictated by our collective ability to apply and iterate upon the foundational lessons from early and ongoing in-depth studies so that we can rationally exploit the cytolytic capabilities of PCVs to eradicate advanced cancer, cure patients in the adjuvant setting, and prevent the development of malignancy in high-risk patients.
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Journal of Clinical Oncology
ADAGIO: A Phase IIb, Open-Label, Single-Arm, Multicenter Study Assessing the Efficacy and Safety of Adavosertib (AZD1775) as Treatment for Recurrent or Persistent Uterine Serous Carcinoma
Liu JF
PURPOSE: This phase IIb, single-arm, multicenter, global study (ADAGIO; ClinicalTrials.gov identifier: NCT04590248) assessed the efficacy and safety of adavosertib in patients with recurrent/persistent uterine serous carcinoma (USC) who had previously received platinum-based chemotherapy.
METHODS: Eligible patients were age 18 years and older and had histologically confirmed recurrent/persistent USC, previously treated with at least one platinum-based chemotherapy regimen, and with evidence of measurable disease. Adavosertib was administered orally at 300 mg once daily on days 1-5 and 8-12 of a 21-day cycle until discontinuation criteria were met. The primary end point was objective response rate (ORR) by blinded independent central review (BICR). Secondary end points included duration of response (DoR), progression-free survival (PFS), safety, and tolerability. Biomarkers previously associated with adavosertib response in other settings were assessed in archival tissue samples.
RESULTS: In 104 evaluable patients, one complete response and 26 partial responses were observed, for an ORR by BICR of 26.0% (95% CI, 17.9 to 35.5). Median DoR was 4.7 months (95% CI, 3.8 to 8.3); median PFS was 2.8 months (95% CI, 2.6 to 3.9). Biomarker analysis identified no single predictive alteration for adavosertib response, although a trend was observed for CCNE1 amplification or high cyclin E1 protein expression. Most patients (97.2%) experienced treatment-related adverse events (TRAEs), most frequently diarrhea (59.6%), nausea (59.6%), and anemia (58.7%). Grade ?3 TRAEs occurred in 60.6% of patients, with neutropenia (21.1%) and fatigue (13.8%) most common. 17.4% of patients discontinued adavosertib due to AEs (treatment-related in 14.7%).
CONCLUSION: Adavosertib showed some antitumor activity in patients with recurrent/persistent USC. However, at 300 mg once daily dosing, it was not well tolerated in this population. Exploratory biomarker studies suggest CCNE1/cyclin E1 expression may enrich for response to Wee1 inhibition in USC.
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Journal of Clinical Oncology
Can Improving Adjuvant Endocrine Therapy Persistence Improve Survival Outcomes for Patients with Early-Stage Breast Cancer?
Tesch ME, Partridge AH
In the early 1990s, an Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis of adjuvant tamoxifen trials in patients with early breast cancer demonstrated significant reductions in the risk of death from breast cancer with tamoxifen in postmenopausal women. However, no clear survival advantage was seen in premenopausal women owing to little data in this subgroup, which, in part, led to tamoxifen routinely not being used in younger patients. An updated EBCTCG meta-analysis later established that 5 years of adjuvant tamoxifen substantially improved survival in both postmenopausal and premenopausal women, bringing into harsh focus the number of lives that could have been saved had the benefits of tamoxifen in younger patients been known sooner. Similarly, it was not until the SOFT/TEXT trials investigated adjuvant aromatase inhibitors (AI) in combination with ovarian function suppression (OFS) for premenopausal breast cancer that young patients became eligible, at last, for treatment with AI, over a decade after AIs had become the preferred adjuvant endocrine therapy (ET) for postmenopausal patients with hormone receptor (HR)-positive breast cancer, given their well-established superiority over tamoxifen. These examples underscore the need for dedicated studies in young adults with breast cancer, in whom the incidence of breast cancer has risen more sharply in recent years and whose survival rates remain lower, as compared with older adults.
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Journal of Clinical Oncology
Neoadjuvant Nivolumab Plus Ipilimumab Versus Chemotherapy in Resectable Lung Cancer
Awad MM, Swanson SJ
PURPOSE: Neoadjuvant immune checkpoint blockade with nivolumab plus ipilimumab improves overall survival (OS) in non-small cell lung cancer (NSCLC); however, randomized data for resectable lung cancer are limited. We report results from the exploratory concurrently randomized nivolumab plus ipilimumab and chemotherapy arms of the international phase III CheckMate 816 trial.METHODS: Adults with stage IB-IIIA (American Joint Committee on Cancer seventh edition) resectable NSCLC received three cycles of nivolumab once every 2 weeks plus one cycle of ipilimumab or three cycles of chemotherapy (on day 1 or days 1 and 8 of each 3-week cycle) followed by surgery. Analyses included event-free survival (EFS), OS, pathologic response, surgical outcomes, biomarker analyses, and safety.
RESULTS: A total of 221 patients were concurrently randomly assigned to nivolumab plus ipilimumab (n = 113) or chemotherapy (n = 108). At a median follow-up of 49.2 months, the median EFS was 54.8 months (95% CI, 24.4 to not reached [NR]) with nivolumab plus ipilimumab versus 20.9 months (95% CI, 14.2 to NR) with chemotherapy (HR, 0.77 [95% CI, 0.51 to 1.15]); 3-year EFS rates were 56% versus 44%. Higher rates of EFS events were initially seen, with later benefit favoring nivolumab plus ipilimumab; 3-year OS rates were 73% versus 61% (HR, 0.73 [95% CI, 0.47 to 1.14]); pathologic complete response rates were 20.4% versus 4.6%, respectively. In the respective arms, 83 (74%) and 82 patients (76%) underwent definitive surgery. Grade 3-4 treatment-related adverse events occurred in 14% and 36% of patients, respectively.
CONCLUSION: Neoadjuvant nivolumab plus ipilimumab showed potential long-term clinical benefit versus chemotherapy, despite early crossing of EFS curves in the preoperative phase and a lower rate of high-grade toxicity.
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Nature
A DNA-Gated Molecular Guard Controls Bacterial Hailong Anti-Phage Defence
Tan JMJ, Cofsky JC, Syangtan D, Hobbs SJ, Del Marmol J, Jost M, Kruse AC, Kranzusch PJ
Animal and bacterial cells use nucleotidyltransferase (NTase) enzymes to respond to viral infection and control major forms of immune signaling including cGAS-STING innate immunity and CBASS anti-phage defence1-4. Here we discover a family of bacterial defence systems, which we name Hailong, that use NTase enzymes to constitutively synthesize DNA signals and guard against phage infection. Hailong protein B (HalB) is an NTase that converts deoxy-ATP into single-stranded DNA oligomers. A series of X-ray crystal structures define a stepwise mechanism of HalB DNA synthesis initiated by a C-terminal tyrosine residue that enables de novo enzymatic priming. We show that HalB DNA signals bind to and repress activation of a partnering Hailong protein A (HalA) effector complex. A 2.0 Å cryo-EM structure of the HalA-DNA complex reveals a membrane protein with a conserved ion channel domain and a unique crown domain that binds the DNA signal and gates activation. Analyzing Hailong defence in vivo, we demonstrate that viral DNA exonucleases required for phage replication trigger release of the primed HalA complex and induce protective host cell growth arrest. Our results explain how inhibitory nucleotide immune signals can serve as molecular guards against phage infection and expand the mechanisms NTase enzymes use to control antiviral immunity.
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Nature Biotechnology
Treatment of Acute Myeloid Leukemia Models by Targeting a Cell Surface RNA-Binding Protein
George BM, Perr J, Chai P, Hemberger H, Lebedenko CG, Yu Q, Bapcum E, Camargo F, Flynn RA
Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterize nucleophosmin (NPM1) as an abundant cell surface protein (csNPM1) on a variety of tumor types. With a focus on AML, we observe csNPM1 on blasts and leukemic stem cells but not on normal hematopoietic stem cells. We develop a monoclonal antibody to target csNPM1, which exhibits robust anti-tumor activity in multiple syngeneic and xenograft models of AML, including patient-derived xenografts, without observable toxicity. We find that csNPM1 is expressed in a mutation-agnostic manner on primary AML cells and may therefore offer a general strategy for detecting and treating AML. Surface profiling and in vivo work also demonstrate csNPM1 as a target on solid tumors. Our data suggest that csNPM1 and its neighboring glycoRNA-cell surface RNA-binding protein (csRBP) clusters may serve as an alternative antigen class for therapeutic targeting or cell identification.
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Nature Communications
Investigative Needle Core Biopsies Support Multimodal Deep-Data Generation in Glioblastoma
Baquer G, Ahn R, Gantchev J, Regan MS, Prabhu MC, D'Souza AD, Malinowski SW, Stopka SA, Couturier C, Chow KH, Yerrum S, Kao PL, Beroukhim R, Frisken S, Brennan C, Reardon DA, Chiocca EA, Ligon KL, White FM, Agar NYR
Glioblastoma (GBM) is an aggressive primary brain cancer with few effective therapies. Stereotactic needle biopsies are routinely used for diagnosis; however, the feasibility and utility of investigative biopsies to monitor treatment response remains ill-defined. Here, we demonstrate the depth of data generation possible from routine stereotactic needle core biopsies and perform highly resolved multi-omics analyses, including single-cell RNA sequencing, spatial transcriptomics, metabolomics, proteomics, phosphoproteomics, T-cell clonotype analysis, and MHC Class I immunopeptidomics on standard biopsy tissue obtained intra-operatively. We also examine biopsies taken from different locations and provide a framework for measuring spatial and genomic heterogeneity. Finally, we investigate the utility of stereotactic biopsies as a method for generating patient-derived xenograft (PDX) models. Multimodal dataset integration highlights spatially mapped immune cell-associated metabolic pathways and validates inferred cell-cell ligand-receptor interactions. In conclusion, investigative biopsies provide data-rich insight into disease processes and may be useful in evaluating treatment responses.
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New England Journal of Medicine
Clonal Hematopoiesis as a Driver of Solid Tumors
Weeks LD, Ebert BL
Clonal hematopoiesis is the expansion of a genetically related population of hematopoietic stem and progenitor cells that disproportionately contribute to blood-cell production. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by mutations in genetic drivers of myeloid cancers, a variant allele fraction of 2% or more, and the absence of cytopenias. CHIP is powerfully associated with the development of myeloid cancers such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The risk of progression from CHIP to MDS or AML varies, and features such as specific mutations, clone size, number of mutations, red-cell variables, and patient age have clear prognostic importance.
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Blood Cancer Journal
Long-Term Outcomes and Clinical Phenotypes Associated With Best Response to Low Dose Alemtuzumab in Cutaneous T-Cell Lymphoma
Larocca C, Bui AN, O'Malley JT, Giobbie-Hurder A, Tawa M, Teague JE, Clark RA, Cutler C, Jacobsen E, Fisher DC, Kupper TS, LeBoeuf NR
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British Journal of Haematology
Development and Characterization of the Novel MYD88 Mutated, 6q Deleted BCWM.2 Cell Line for Waldenström Macroglobulinaemia
Liu S, Liu X, Yusuf CFB, Kofides A, Soroko KM, Penailillo J, Canning AG, Cao Y, Yang G, Xu L, Tsakmaklis N, Sun H, Guijosa A, Guerrera ML, Patterson CJ, Carrasco RD, Gokhale PC, Sarosiek SR, Castillo JJ, Hatcher JM, Hunter ZR, Treon SP
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Cell Reports
LncRNA SLNCR Phenocopies the E2F1 DNA Binding Site to Promote Melanoma Progression
Shah K, Anastasakou E, Sejour L, Wang Y, Wert-Lamas L, Rauchet C, Studer S, Goller S, Distel RJ, Marasco W, Vlachos IS, Novina CD
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Clinical Cancer Research
Factors Associated with Disease Progression after Discontinuation of Immune Checkpoint Inhibitors for Immune-Related Toxicity in Patients with Advanced Non-Small Cell Lung Cancer
Pecci F, Alden SL, Ricciuti B, Alessi JV, Wang X, Vaz VR, Barrichello A, Lamberti G, Di Federico A, Santo V, Rossato de Almeida G, Gandhi M, Nishino M, Johnson BE, Awad MM
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European Journal of Nuclear Medicine and Molecular Imaging
A Pilot Study of [(18)F]F-Fluciclovine Positron Emission Tomography/Computed Tomography for Staging Muscle Invasive Bladder Cancer Preceding Radical Cystectomy
Ng TSC, Liu M, Robertson M, Könik A, Cheng SC, Bakht MK, Harrington K, Wolanski A, Gilbert L, Preston M, Mossanen M, Beltran H, Hirsch MS, Sonpavde G, Jacene HA
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