Blood
Abatacept for Acute Graft-Versus-Host Disease Prophylaxis After Unrelated Donor Hematopoietic Cell Transplantation
Kean LS, Bratrude B, Betz K
Abatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first US Food and Drug Administration (FDA)-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URD-HCT). Using Center for International Blood and Marrow Transplant Research data, we investigated its impact in patients receiving 7/8 HLA-mismatched unrelated donor (MMUD) or 8/8 HLA-matched unrelated donor (MUD) URD-HCT between 2011 and 2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapse-free survival (RFS) for abatacept + CNI/MTX vs CNI/MTX, CNI/MTX + antithymocyte globulin (ATG), and posttransplant cyclophosphamide-based prophylaxis (PT-Cy). For 7/8 MMUDs, day-180 OS (primary end point supporting FDA approval) was significantly higher for abatacept + CNI/MTX vs CNI/MTX (98% vs 75%; P = .0028). Two-year RFS was significantly higher for abatacept + CNI/MTX vs CNI/MTX (74% vs 49%; P = .0098) and CNI/MTX + ATG (77% vs 35%; P = .0002), and similar vs PT-Cy (72% vs 56%; P = .1058). For 8/8 MUDs, 2-year RFS for abatacept + CNI/MTX was numerically higher vs CNI/MTX (63% vs 52%; P = .1497), with an improved hazard ratio (HR) of 0.46 (0.25-0.86), and vs CNI/MTX + ATG (66% vs 55%; P = .1193; HR, 0.39 [0.21-0.73]), and was similar vs PT-Cy (68% vs 57%; P = .2356; HR, 0.54 [0.26-1.11]). For 7/8 MMUD and 8/8 MUD recipients, abatacept + CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX + ATG; outcomes were similar to PT-Cy-based regimens. Abatacept + CNI/MTX may facilitate unrelated donor pool expansion for HCT.
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JAMA Oncology
Dual Immune Checkpoint Inhibition in Patients with Aggressive Thyroid Carcinoma: A Phase 2 Nonrandomized Clinical Trial
Sehgal K, Pappa T, Shin KY, Schiantarelli J, Liu M, Ricker C, Besson NR, Jones SM, Welsh EL, Pfaff KL, Barletta JA, Park J, Reardon B, Doherty GM, Alexander EK, Rodig SJ, Barbie DA, O'Neill A, Van Allen E, Haddad RI, Lorch JH
IMPORTANCE: Aggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition.
OBJECTIVE: To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma.
DESIGN, SETTING, AND PARTICIPANTS: This phase 2 nonrandomized clinical trial enrolled patients with RAIR DTC in a single center from October 2017 to May 2019, with exploratory cohorts in MTC and ATC. The data were analyzed between June 2021 and September 2023.
INTERVENTION: Intravenous nivolumab, 3 mg/kg, every 2 weeks and ipilimumab, 1 mg/kg, every 6 weeks until disease progression, intolerable adverse events, or a maximum duration of 2 years.
MAIN OUTCOMES AND MEASURES: The primary end point of the study was objective response rate (ORR) in RAIR DTC, which was scored according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1. Key secondary end points included safety, progression-free survival, overall survival, and biomarker analyses.
RESULTS: A total of 51 patients were registered, and 49 patients were evaluable for analysis. The median (range) age was 65 years (30-88 years), and 25 participants (51%) were female. ORR in the DTC cohort was 9.4% (3/32 [95% CI, 2.8%-28.5%]), with all partial responses in either oncocytic carcinoma (2/6 [33.0%]) or poorly differentiated thyroid carcinoma (1/5 [20.0%]). Clinical benefit rates were 62.5% (20/32) in the overall DTC cohort, including 83.3% (5/6) in oncocytic carcinoma and 40% (2/5) in poorly differentiated thyroid carcinoma. ORR in the exploratory ATC cohort was 30.0% (3/10 [95% CI, 6.7%-65.2%]), with a clinical benefit rates of 50.0% (5/10). No responses were observed in the exploratory MTC cohort. The safety profile was similar to prior reports with dual immune checkpoint inhibition (pruritus, rash, diarrhea, fatigue, and elevation of lipase and liver enzymes). The presence of NRAS tumor genetic sequence variations, but not BRAF V600E, was associated with worse outcomes.
CONCLUSIONS AND RELEVANCE: This phase 2 nonrandomized clinical trial reported clinical activity of dual immune checkpoint inhibition in aggressive thyroid cancer. The study did not meet its end point in the primary population of RAIR DTC and does not support further investigation in non-biomarker-selected DTC. However, the signal observed in ATC may merit further evaluation.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03246958.
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Nature Medicine
A Multi-Modal Single-Cell and Spatial Expression Map of Metastatic Breast Cancer Biopsies Across Clinicopathological Features
Klughammer J, Abravanel DL, Segerstolpe Å, Blosser TR, Ashenberg O, Slyper M, Vigneau S, Jané-Valbuena J, Alon S, Caraccio C, Chen J, Cohen O, Cullen N, DelloStritto LK, Dionne D, Files J, Frangieh A, Helvie K, Hughes ME, Inga S, Kanodia A, Lako A, MacKichan C, Mages S, Murray E, Napolitano S, Nguyen K, Ortiz R, Patel M, Pfaff KL, Porter CBM, Rotem A, Strauss S, Thorner AR, Turner M, Wakiro I, Waldman J, Wu J, Gómez Tejeda Zañudo J, Zhang D, Lin NU, Tolaney SM, Winer EP, Chen F, Rodig SJ, Zhuang X, Rozenblatt-Rosen O, Johnson BE, Regev A, Wagle N
Although metastatic disease is the leading cause of cancer-related deaths, its tumor microenvironment remains poorly characterized due to technical and biospecimen limitations. In this study, we assembled a multi-modal spatial and cellular map of 67 tumor biopsies from 60 patients with metastatic breast cancer across diverse clinicopathological features and nine anatomic sites with detailed clinical annotations. We combined single-cell or single-nucleus RNA sequencing for all biopsies with a panel of four spatial expression assays (Slide-seq, MERFISH, ExSeq and CODEX) and H&E staining of consecutive serial sections from up to 15 of these biopsies. We leveraged the coupled measurements to provide reference points for the utility and integration of different experimental techniques and used them to assess variability in cell type composition and expression as well as emerging spatial expression characteristics across clinicopathological and methodological diversity. Finally, we assessed spatial expression and co-localization features of macrophage populations, characterized three distinct spatial phenotypes of epithelial-to-mesenchymal transition and identified expression programs associated with local T cell infiltration versus exclusion, showcasing the potential of clinically relevant discovery in such maps.
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Proceedings of the National Academy of Sciences U.S.A.
Biochemical Analysis of EGFR Exon20 Insertion Variants InsASV and InsSVD and Their Inhibitor Sensitivity
Zhao H, Beyett TS, Jiang J, Rana JK, Schaeffner IK, Santana J, Jänne PA, Eck MJ
Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non-small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely respond to EGFR tyrosine kinase inhibitors (TKIs). Therefore, there is a significant need to develop inhibitors that are active against this class of activating mutations. Here, we conducted biochemical analysis of the two most frequent exon 20 insertion variants, V769_D770insASV (insASV) and D770_N771insSVD (insSVD) to better understand their drug sensitivity and resistance. From kinetic studies, we found that EGFR insASV and insSVD are similarly active, but have lower Km, ATP values compared to the L858R variant, which contributes to their lack of sensitivity to 1st-3rd generation EGFR TKIs. Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants.
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Blood Advances
Inhibition of MICA and MICB Shedding Enhances Memory-Like NK-Cell-Mediated Cytotoxicity Against Multiple Myeloma
Tahri S, Piccinelli S, Su NK, Lampe L, Dong H, Vergara Cadavid J, Boiarsky R, Lightbody ED, Cao A, Alberge JB, Rahmat M, Shen Y, Getz G, Wucherpfennig KW, Ghobrial IM, Romee R
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Blood Cancer Journal
Venous Thromboembolism in Adolescents and Young Adults with Acute Lymphoblastic Leukemia Treated on a Pediatric-Inspired Regimen
Shimony S, Raman HS, Flamand Y, Keating J, Paolino JD, Place AE, Silverman LB, Sallan SE, Vrooman LM, Brunner AM, Neuberg DS, Galinsky I, Garcia JS, Winer ES, Wadleigh M, Stone RM, Connors JM, DeAngelo DJ, Luskin MR
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Breast Cancer Research and Treatment
Patient-Reported Outcomes, and Perceptions and Knowledge About Recurrence in Women with Hormone Receptor-Positive Breast Cancer
Rosenberg SM, Zheng Y, Santos K, Riley E, Meadows HW, Snow C, Hughes ME, Frank E, Lin NU, Partridge AH, Winer EP, Parsons HA
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Cell Chemical Biology
Small Molecules Targeting Selective PCK1 and PGC-1? Lysine Acetylation Cause Anti-Diabetic Action Through Increased Lactate Oxidation
Mutlu B, Sharabi K, Sohn JH, Yuan B, Latorre-Muro P, Qin X, Yook JS, Yu D, Kajimura S, Hui S, Puigserver P
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Clinical Cancer Research
A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors
Cote GM, Kochupurakkal BS, Do K, Bullock A, Muzikansky A, McLoughlin DE, Cleary JM, Gao X, Parikh A, Park JC, Weekes CD, Yeku O, Shapiro GI
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Journal of Geriatric Oncology
Smartphone Application for Longitudinal Home Gait Speed Measurement in Older Adults with Blood Cancers: A Feasibility and Acceptability Study
Lee PA, DuMontier C, Groblewski N, Yu W, Zhou J, Hshieh T, Kim D, Travison T, Driver J, Lo OY, Manor B, Abel G
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