Welcome to Dana-Farber's Research News
September 15, 2023
This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: Michael_buller@dfci.harvard.edu.
Blood
A Road Map for Navigating CAR T Hematotoxicity
Jacobson C
In this issue of Blood, Rejeski et al, representing an international panel of experts from the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT), review available data on chimeric antigen receptor (CAR) T cell–associated cytopenias, which they define as immune effector cell–associated hematotoxicity (ICAHT), and assemble recommendations on grading, predicting, preventing, evaluating, and managing ICAHT.
Blood
Armand P, Shipp MA
Previous analyses of the phase 2 KEYNOTE-087 (NCT02453594) trial of pembrolizumab monotherapy demonstrated effective antitumor activity with acceptable safety in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). However, long-term response durability and outcome of patients who receive a second course after treatment discontinuation after complete response (CR) remain of clinical interest. We present KEYNOTE-087 data after >5 years of median follow-up. Patients with R/R cHL and progressive disease (PD) after autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV; cohort 1), salvage chemotherapy and BV without ASCT (cohort 2), or ASCT without subsequent BV (cohort 3), received pembrolizumab for ?2 years. Patients in CR who discontinued treatment and subsequently experienced PD were eligible for second-course pembrolizumab. Primary end points were the objective response rate (ORR) using blinded central review and safety. The median follow-up was 63.7 months. ORR was 71.4% (95% confidence interval [CI], 64.8-77.4; CR, 27.6%; partial response, 43.8%). Median duration of response (DOR) was 16.6 months; median progression-free survival was 13.7 months. A quarter of responders, including half of complete responders, maintained a response for ?4 years. Median overall survival was not achieved. Among 20 patients receiving second-course pembrolizumab, ORR for 19 evaluable patients was 73.7% (95% CI, 48.8-90.8); median DOR was 15.2 months. Any-grade treatment-related adverse events occurred in 72.9% of patients and grade 3 or 4 adverse events occurred in 12.9% of patients; no treatment-related deaths occurred. Single-agent pembrolizumab can induce durable responses, particularly in patients achieving CR. Second-course pembrolizumab frequently reinduced sustained responses after relapse from initial CR.
Cancer Discovery
Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multi-Cancer Biomarker
Taylor MS, Zhang SJ, Senussi Y, Cajuso T, Cheng WC, Heaps JD, Miller BD, Cohen L, Bhan I, Yang X, Taplin ME, Wang X, Christiani DC, Johnson BE, Meyerson M, Uppaluri R, Egloff AM, Denault EN, Spring LM, Yilmaz OH, Cohen S, Sharova T, Chi G, Norden BL, Song Y, Nieman LT, Pappas L, Parikh AR, Strickland MR, Corcoran RB, Eng G, Matulonis UA, Skates SJ, Rueda BR, Klempner SJ, Deshpande V, Ting DT, Walt DR, Burns KH
Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. While proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10-17 M) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multi-analyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multi-cancer biomarker with potential utility for disease detection and monitoring.
Journal of Clinical Oncology
Jänne PA
PURPOSE: Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC).
METHODS: This phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced EGFR-mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 ? 4.8 ? 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data.
RESULTS: Enrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations.
CONCLUSION: After tumor progression with EGFR TKI therapy and PBC in patients with EGFR-mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR-mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).
Journal of Clinical Oncology
Mullen EA
PURPOSE: The safety of reintroducing chemotherapy in the pediatric renal tumor setting after severe hepatopathy (SH), including sinusoidal obstruction syndrome (SOS), is uncertain. We describe the incidence, severity, outcomes, and impact on subsequent treatment for patients with SH from National Wilms Tumor Study (NWTS) protocols 3-5.
PATIENTS AND METHODS: Archived charts for patients enrolled on NWTS 3-5 who met study inclusion criteria for SH by using established hepatopathy grading scales and clinical criteria were reviewed for demographics, tumor characteristics, radio- and chemotherapy details, SH-related dose modifications, and oncologic outcomes. Genomic analysis for candidate polymorphisms associated with SH was performed in 14 patients.
RESULTS: Seventy-one of 8,862 patients (0.8%) met study inclusion criteria. The median time from therapy initiation to SH was 51 days (range, 2-293 days). Sixty percent received radiotherapy, and 56% had right-sided tumors. Grade 1-4 thrombocytopenia was noted in 70% at initial occurrence of SH (median 22,000/microliter). Among 69 of 71 children with SH occurring before the end of therapy (EOT) and post-SH treatment information available, chemotherapy was delayed posthepatopathy for 65% (69% of these at a reduced dose), continued without delay for 20% (57% of these at reduced dose), and stopped completely for 15% (4 of 10 of whom died of SH). Overall, 42% of patients with dose reductions achieved full dose by EOT. The five-year post-SH event-free survival for patients who continued therapy was 89% (95% CI, 81 to 98), with no significant differences by whether delay or dose reduction occurred. We identified no SH-associated pharmacogenomic polymorphism.
CONCLUSION: The incidence of SH on NWTS 3-5 was low; many had associated severe thrombocytopenia. Careful reintroduction of chemotherapy appeared to be feasible for the majority of patients who developed severe chemotherapy- and/or radiotherapy-induced liver toxicity.
Journal of Clinical Oncology
Jänne PA
PURPOSE: Trastuzumab deruxtecan (T-DXd) 5.4 and 6.4 mg/kg showed robust antitumor activity in multiple cancer indications; however, T-DXd 5.4 mg/kg has not been evaluated in patients with previously treated human epidermal growth factor receptor 2-mutant (HER2m; defined as single-nucleotide variants and exon 20 insertions) metastatic non-small-cell lung cancer (mNSCLC).
METHODS: DESTINY-Lung02, a blinded, multicenter, phase II study, investigated T-DXd 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with HER2m mNSCLC and further assessed T-DXd 6.4 mg/kg once every 3 weeks in this population. The primary end point was confirmed objective response rate (ORR) per RECIST v1.1 by blinded independent central review.
RESULTS: One hundred fifty-two patients were randomly assigned 2:1 to T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. As of December 23, 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. Confirmed ORR was 49.0% (95% CI, 39.0 to 59.1) and 56.0% (95% CI, 41.3 to 70.0) and median duration of response was 16.8 months (95% CI, 6.4 to not estimable [NE]) and NE (95% CI, 8.3 to NE) with 5.4 and 6.4 mg/kg, respectively. Median treatment duration was 7.7 months (range, 0.7-20.8) with 5.4 mg/kg and 8.3 months (range, 0.7-20.3) with 6.4 mg/kg. Grade ? 3 drug-related treatment-emergent adverse events occurred in 39 of 101 (38.6%) and 29 of 50 (58.0%) patients with 5.4 and 6.4 mg/kg, respectively. 13 of 101 (12.9%) and 14 of 50 (28.0%) patients had adjudicated drug-related interstitial lung disease (2.0% grade ? 3 in each arm) with 5.4 and 6.4 mg/kg, respectively.
CONCLUSION: T-DXd demonstrated clinically meaningful responses at both doses. Safety profile was acceptable and generally manageable, favoring T-DXd 5.4 mg/kg.
Journal of the National Cancer Institute
Molecular Features of Prostate Cancer Post-Neoadjuvant Therapy in the Phase 3 CALGB 90203 Trial
Mizuno K, Ku S, Taplin ME, Beltran H
PURPOSE: The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy (CHT) for high-risk localized PCa before radical prostatectomy (RP). We dissect the molecular features of post-treated PCa along with long-term clinical outcomes to explore mechanisms of response and resistance to CHT.
PATIENTS AND METHODS: We evaluated 471?RP tumors, including 294 samples from 166 patients treated with 6 cycles of docetaxel plus androgen deprivation therapy prior to RP, and 177 samples from 97 patients in the control arm of RP alone. Targeted DNA sequencing and mRNA expression of tumor foci and adjacent non-cancer regions were analyzed in conjunction with pathologic changes and clinical outcomes.
RESULTS: Tumor fraction estimated from DNA sequencing was significantly lower in CHT-exposed tissues compared to control. Higher tumor fraction after CHT was associated with aggressive pathologic features and poor outcomes including PSA progression-free survival. SPOP mutations were infrequently detected after CHT, while TP53 mutations were enriched and associated with shorter overall survival. Residual tumor fraction post-CHT was linked with higher expression of androgen receptor-regulated, cell cycle, and neuroendocrine genes, suggesting persistent populations of active PCa cells. Supervised clustering of post-CHT high tumor
fraction tissues identified a group of patients with elevated cell cycle-related gene expression and poor clinical outcomes.
CONCLUSIONS: Distinct recurrent PCa genomic and transcriptomic features are observed after CHT exposure. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 mutations and high cell cycle transcriptomic activity are linked with aggressive residual disease despite potent CHT.
JAMA Oncology
Right-Sizing Models of Genetic Cancer Predisposition Testing
Rana HQ, Garber JE
Inherited cancer susceptibility testing began with the cloning of BRCA1 and BRCA2 in the early 1990s modeled on previously active programs for polycystic kidney disease and Huntington disease. They both used genetic counselors to educate individuals about the reasons to consider or decline testing, with emphasis on informed decision-making, patient autonomy, and concerns about potential adverse effects of learning that inherited predisposition was present. Thirty years later, multiple alternative models have been implemented, most for expediency because of the relative paucity of genetic counselors or the restrictions conferred by the COVID-19 pandemic, but without evaluation of the multiple deviations from the thoroughly assessed programs for BRCA1/2, Lynch syndrome, and many others.
Nature
Epitope Editing Enables Targeted Immunotherapy of Acute Myeloid Leukaemia
Casirati G, Cosentino A, Mucci A, Salah Mahmoud M, Ugarte Zabala I, Zeng J, Ficarro SB, Klatt D, Brendel C, Ritz J, Marto JA, Pellin D, Bauer DE, Armstrong SA, Genovese P
Despite the considerable efficacy observed when targeting a dispensable lineage antigen, such as CD19 in B cell acute lymphoblastic leukaemia1,2, the broader applicability of adoptive immunotherapies is hampered by the absence of tumour-restricted antigens3-5. Acute myeloid leukaemia immunotherapies target genes expressed by haematopoietic stem/progenitor cells (HSPCs) or differentiated myeloid cells, resulting in intolerable on-target/off-tumour toxicity. Here we show that epitope engineering of donor HSPCs used for bone marrow transplantation endows haematopoietic lineages with selective resistance to chimeric antigen receptor (CAR) T cells or monoclonal antibodies, without affecting protein function or regulation. This strategy enables the targeting of genes that are essential for leukaemia survival regardless of shared expression on HSPCs, reducing the risk of tumour immune escape. By performing epitope mapping and library screenings, we identified amino acid changes that abrogate the binding of therapeutic monoclonal antibodies targeting FLT3, CD123 and KIT, and optimized a base-editing approach to introduce them into CD34+ HSPCs, which retain long-term engraftment and multilineage differentiation ability. After CAR T cell treatment, we confirmed resistance of epitope-edited haematopoiesis and concomitant eradication of patient-derived acute myeloid leukaemia xenografts. Furthermore, we show that multiplex epitope engineering of HSPCs is feasible and enables more effective immunotherapies against multiple targets without incurring overlapping off-tumour toxicities. We envision that this approach will provide opportunities to treat relapsed/refractory acute myeloid leukaemia and enable safer non-genotoxic conditioning.
Nature Biotechnology
Author Correction: Massively Parallel Single-Cell Mitochondrial DNA Genotyping and Chromatin Profiling
Lareau CA, Ludwig LS, Muus C, Gohil SH, Zhao T, Chiang Z, Pelka K, Verboon JM, Luo W, Christian E, Rosebrock D, Getz G, Boland GM, Chen F, Buenrostro JD, Hacohen N, Wu CJ, Aryee MJ, Regev A, Sankaran VG
In the version of this article initially published, due to a coding error, cell clonotypes and allele frequencies were permuted, impacting the visualization of panels in Fig. 6i, j, k, and o. Corrected panels appear as Fig. 1 below, and the software and documentation listed in the Code availability section have been updated. Interpretations of the data or text in the paper were not impacted by this issue. The figure has been corrected in the HTML and PDF versions of the article.
Nature Cell Biology
KDM6A Epigenetically Regulates Subtype Plasticity in Small Cell Lung Cancer
Duplaquet L, Li Y, Booker MA, Xie Y, Olsen SN, Hong D, Hatton C, Denize T, Walton E, Laimon YN, Li R, Jiang Y, Bronson RT, Southard J, Li S, Signoretti S, Qiu X, Cejas P, Armstrong SA, Long HW, Tolstorukov MY, Oser MG
Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.
Nature Communications
Publisher Correction: Cryo-EM Structure of a RAS/RAF Recruitment Complex
Park E, Rawson S, Schmoker A, Kim BW, Oh S, Jeon H, Eck MJ
The original version of this Article contained errors in Table 1. The correct version of the final row of the 2nd column states ‘127.3?±?77.2’ instead of the original, incorrect ‘±77.2’. The correct version of the final column of the 2nd row states ‘21.2 (ref. 24) 356 (ref. 17)’ instead of the original, incorrect ‘21.2 (ref. 24, 356 (ref. 17)’; the correct version of the final column of the 3rd row states ‘190.5 (ref. 24) 152 (ref. 17)’ instead of the original, incorrect ‘190.5 (ref. 24, 152 (ref. 17)’.This has been corrected in both the PDF and HTML versions of the Article.
New England Journal of Medicine
Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma
Richardson PG
BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide.
METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1.
RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9).
CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).
New England Journal of Medicine
Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma
Wen PY
Background: Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas.
Methods: In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed.
Results: A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo.
Conclusions: In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention.
Science Immunology
Preexisting Tumor-Resident T Cells with Cytotoxic Potential Associate with Response to Neoadjuvant Anti-PD-1 in Head and Neck Cancer
Oliveira G, Egloff AM, Afeyan AB, Wolff JO, Zeng Z, Zhou L, Messier C, Lizotte P, Pfaff KL, Stromhaug K, Penter L, Haddad RI, Hanna GJ, Schoenfeld JD, Goguen LA, Annino DJ, Jo V, Webb J, Fu J, Dunn GP, Rodig SJ, Paweletz CP, Wu CJ, Uppaluri R
About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (?50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting.
Science Immunology
The HLA Advantage: Why COVID-19 Benched You but Not Your Co-Worker
Saif N, Griffin GK
An HLA variant confers protective immunity against COVID-19 through cross-reactive T cells induced by seasonal coronaviruses.
Nature Communications
Spisak S, Tisza V, Nuzzo PV, Seo JH, Sztupinszki Z, Bell C, Rohanizadegan M, Stillman DR, Alaiwi SA, Bartels AB, Shetty A, Pomerantz M, Baca S, Szallasi Z, Gusev A, Freedman ML
To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.
Annals of Surgical Oncology
ASO Visual Abstract: Genomic Characterization of Aggressive Breast Cancer in Younger Women
Franco I, Punglia R
Annals of Surgical Oncology
Glass CC, Pride RM, Freedman RA, Mayer EL, Ogayo ER, King TA, Mittendorf EA, Kantor O
Blood Advances
Merryman RW, Redd RA, Taranto E, Jeter E, McHugh KM, Brown JR, Crombie JL, Davids MS, Fisher DC, Freedman AS, Jacobsen E, Jacobson CA, Kim AI, LaCasce AS, Ng SY, Odejide OO, Parry EM, Jacene H, Park H, Joyce RM, Chen YB, Shipp MA, Armand P
BMC Bioinformatics
Empirical Evaluation of Language Modeling to Ascertain Cancer Outcomes from Clinical Text Reports
Elmarakeby HA, Trukhanov PS, Riaz IB, Van Allen EM, Kehl KL
CA: A Cancer Journal for Clinicians
Haddox CL, Baldini EH, Jagannathan JP, Hornick JL, Raut CP
Cancer Treatment Reviews
Haddad RI
Clinical Cancer Research
Mutual ATRaction: Assessing Synergy of Berzosertib with Sacituzumab Govitecan
Berg SA, Choudhury AD
Clinical Gastroenterology and Hepatology
Being Breastfed in Infancy and Risk of Colorectal Cancer and Precursor Lesions
Yuan C, Wang QL, Kim H, Babic A, Zhang J, Wolpin BM, Wu K, Song M, Ogino S, Meyerhardt JA, Chan AT, Giovannucci EL, Ng K
Digestive Diseases and Sciences
Yurgelun MB
Endocrine-Related Cancer
IGF-1 Axis Changes with ADT and Docetaxel in Metastatic Prostate Cancer
Ravi P, Wang V, Fichorova RN, McGregor B, Wei XX, Basaria S
Expert Reviews of Anticancer Therapy
Tolaney SM, Tarantino P
Genome Medicine
Interplay of Mendelian and Polygenic Risk Factors in Arab Breast Cancer Patients
Chu H, Camp SY, Han S, Gillani R, Van Allen EM, AlDubayan SH
International Journal of Radiation Oncology, Biology, Physics
Bitterman DS, Goldner E, Finan S, Harris D, Mak RH, Miller T, Savova GK
JCO Oncology Practice
Evolution of the Oncologist Clinician Educator
Kiel L, Florez N
JCO Oncology Practice
Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update Q&A
Pirl W, Nekhlyudov L
JCO Oncology Practice
Horiguchi M, Abuali I, Florez N
JCO Oncology Practice
Ali AlJabban A, Paik H, Aster JC, Berliner N, Brouillard J, Brown JR, Burns KH, Castillo JJ, Card J, Dal Cin P, DeAngelo DJ, Dorfman DM, Ebert BL, Garcia JS, Jacobson CA, Lakhani H, Laubach JP, Ligon AH, Lindsley RC, Lovitch SB, Luskin MR, Morgan EA, Petrides A, Pinkus GS, Pozdnyakova O, Stone RM, Winer ES, Kim AS
JCO Oncology Practice
Parent Penalty: Parental Leave Experiences of Trainees and Early-Career Faculty in Oncology Subspecialties
Wei Z, Kiel L, Florez N
Journal of General Virology
RNase L-Activating 2'-5' Oligoadenylates Bind ABCF1, ABCF3 and Decr-1
Govande AA, Kranzusch PJ
Journal of Geriatric Oncology
Castillo JJ
Journal of Nuclear Medicine Technology
Liu M, Cheng SC, Abbott A, Dubey S, Van den Abbeele AD, Overmoyer B, Jacene H
Journal of Pain and Symptom Management
Rosenberg AR
Journal of Pain and Symptom Management
Patient-Reported Outcome Benefits for Children with Advanced Cancer and Parents: A Qualitative Study
Merz A, Feifer D, Avery M, Tsuchiyose E, Eche I, Awofeso O, Wolfe J, Dussel V, Requena ML
Journal of Thoracic Oncology
Chasing EGFR Mutations in the Plasma of Patients With Resected NSCLC: Lessons in the ADAURA Era
Facchinetti F, Jänne PA
Journal of Virology
Zhang Z, Wang Q, Nguyen HT, Sodroski JG
Lancet Haematology
Addition of Daratumumab to Lenalidomide, Bortezomib, and Dexamethasone for Transplantation-Eligible Patients with Newly Diagnosed Multiple Myeloma (GRIFFIN): Final Analysis of an Open-Label, Randomised, Phase 2 Trial
Laubach J, Richardson PG
Lancet Haematology
Kelkar AH, Shimony S, Cliff ERS, Stone RM
Leukemia
Rizq O, Tai YT, Anderson KC
Leukemia and Lymphoma
Localized Upper Extremity Edema Secondary to Bruton's Tyrosine Kinase Inhibition
Leung BW, Fay CJ, Said JT, Sheets AR, Lian CG, Brown JR, Castillo JJ, Sarosiek S, Flynn C, LeBoeuf NR
Medical Physics
Monte Carlo Model of a Prototype Flat-Panel Detector for Multi-Energy Applications in Radiotherapy
Ozoemelam I, Myronakis M, Harris TC, Jacobson MW, Hu YH, Berbeco RI
Medical Physics
King MT, Kehayias CE, Chaunzwa T, Rosen DB, Mahal AR, Wallburn TD, Milligan MG, Dyer MA, Nguyen PL, Orio PF, Harris TC, Buzurovic I, Guthier CV
Molecular Therapy - Methods and Clinical Development
Klatt D, Brendel C, Bauer DE
Nature Nanotechnology
Detappe A, Nguyen HV, Agius MP, Mathieu C, Su NK, Ghobrial IM, Ghoroghchian PP, Johnson JA
Nature Reviews Cancer
Bacteria in Cancer Initiation, Promotion and Progression
El Tekle G, Garrett WS
Nature Reviews Immunology
Clonal Haematopoiesis and Dysregulation of the Immune System
Belizaire R, Wong WJ, Robinette ML, Ebert BL
Nature Structural and Molecular Biology
Dynamics of the DYNLL1-MRE11 Complex Regulate DNA End Resection and Recruitment of Shieldin to DSBs
Swift ML, Zhou R, Syed A, Moreau LA, Konstantinopoulos PA, D'Andrea AD, He YJ, Chowdhury D
Neuro-Oncology
Tobochnik S, Wen PY
Neuro-Oncology
The INDIGO Trial: Precision Medicine Finally Comes to Glioma
Shi DD, Kaelin WG
NPJ Precision Oncology
Evolution of Structural Rearrangements in Prostate Cancer Intracranial Metastases
Beltran H
Nucleic Acids Research
Novobiocin Blocks Nucleic Acid Binding to Pol? and Inhibits Stimulation of its ATPase Activity
Syed A, Patterson-Fortin J, Ravindranathan R, Zhou J, D'Andrea AD
Oncologist
Access to High-Quality Hospice Care in a For-Profit World
Odejide OO
Pediatric Blood and Cancer
Children's Oncology Group's 2023 Blueprint for Research: Bone Tumors
DuBois SG, Janeway KA
Pediatric Blood and Cancer
Children's Oncology Group's 2023 Blueprint for Research: Liver Tumors
O'Neill AF
Pediatric Blood and Cancer
Children's Oncology Group's 2023 Blueprint for Research: Renal Tumors
Mullen EA
Pediatrics
Increasing COVID-19 Vaccination Rates for Children With Sickle Cell Disease
Yan AP, Archer NM, Arnold D, Hansbury E, Heeney MM, Johnson D, Lichtman E, McMullan H, Morrissey L, Ilowite M
Radiographics
Hepatobiliary Scintigraphy: A Case-based Review
Mario J, Dietsche E, Schneider A, Sakellis C, Jacene H, Shah H
Supportive Care in Cancer
Integrating Evidence-Based Communication Principles into Routine Cancer Care
Rosenberg AR
Transplantation and Cellular Therapy
Cell Therapy Informatics: Updates on the Integration of HCT/IEC Functionalities into an Electronic Medical Record System in the US to Promote Efficiency, Patient Safety, Research, and Data Interoperability
Ho VT
Transplantation and Cellular Therapy
Children Are Not Just Small Adults
Antin JH
Transplantation and Cellular Therapy
Positive Psychological Well-Being in Hematopoietic Stem Cell Transplantation Survivors
Amonoo HL, Daskalakis E, Deary EC, Celano C, Onyeaka HK, Newcomb R, Barata A, Horick N, Cutler C, Pirl WF, Huffman JC, El-Jawahri A
Transplantation and Cellular Therapy
Survivors of Pediatric Hematopoietic Stem Cell Transplant Exhibit Progressive Diastolic Dysfunction Over Years of Follow-up
Harrison DJ, Daly KP, Gauvreau K, Epstein SF, Walsh ML, Colan S, Duncan C, Lehmann L, Chen MH
Trends in Cancer
Clinical and Translational Relevance of Intratumor Heterogeneity
Goyette MA, Lipsyc-Sharf M, Polyak K