Annals of Oncology
Is Adjuvant Ribociclib Ready for Prime Time?
Natarajan A, Tolaney SM
In 2021, data from the monarchE trial led to the FDA approval of adjuvant abemaciclib in combination with endocrine therapy (ET) for patients with high-risk hormone receptor positive (HR+) early breast cancer (EBC). Slamon et al recently published data from the NATALEE trial, which examined the efficacy of adjuvant ribociclib in HR+ EBC. These data leave us with the question: are we ready to incorporate ribociclib in routine clinical practice and if so, in whom?
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Blood
Baseline Immune State and T-cell Clonal Kinetics are Associated with Durable Response to CAR-T Therapy in Large B-Cell Lymphoma
Maurer K, Grabski IN, Houot R, Gohil SH, Miura S, Redd RA, Lyu H, Lu W, Arihara Y, McDonough M, Ansuinelli M, Reynolds CG, Jacene H, Li S, Livak KJ, Ritz J, Neuberg DS, Irizarry RA, Armand P, Wu CJ, Jacobson CA
Engineered cellular therapy with CD19-targeting chimeric antigen receptor T-cells (CAR-T) has revolutionized outcomes for patients with relapsed/refractory Large B-Cell Lymphoma (LBCL), but the cellular and molecular features associated with response remain largely unresolved. We analyzed serial peripheral blood samples ranging from day of apheresis (day -28/baseline) to 28 days after CAR-T infusion from 50 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) by integrating single cell RNA and TCR sequencing (scRNA-seq/scTCR-seq), flow cytometry, and mass cytometry (CyTOF) to characterize features associated with response to CAR-T. Pretreatment patient characteristics associated with response included presence of B cells and increased lymphocyte-to-monocyte ratio (ALC/AMC). Infusion products from responders were enriched for clonally expanded, highly activated CD8+ T cells. We expanded these observations to 99 patients from the ZUMA-1 cohort and identified a subset of patients with elevated baseline B cells, 80% of whom were complete responders. We integrated B cell proportion ?0.5% and ALC/AMC ?1.2 into a two-factor predictive model and applied this model to the ZUMA-1 cohort. Estimated progression free survival (PFS) at 1 year in patients meeting one or both criteria was 65% versus 31% for patients meeting neither criterion. Our results suggest that patients' immunologic state at baseline affects likelihood of response to CAR-T through both modulation of the T cell apheresis product composition and promoting a more favorable circulating immune compartment prior to therapy. These baseline immunologic features, measured readily in the clinical setting prior to CAR-T, can be applied to predict response to therapy.
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Blood
Therapy Response in AML: A Tale of Two T Cells
Wu CJ
In this issue of Blood, Mazziotta et al investigate CD8+ T-cell subpopulations as correlates with response to induction chemotherapy in acute myeloid leukemia (AML) and identify opposing roles of early memory vs terminally differentiated “senescence-like” cells. The past years have seen ground-breaking progress in immune-based treatment approaches for lymphoid blood malignancies, including chimeric antigen receptor T cells and bispecific antibodies directed against B-cell–lineage markers in acute lymphoblastic leukemia and multiple myeloma, or therapeutic disruption of the PD-1/PD-L1 axis in Hodgkin lymphoma. On the other hand, myeloid malignancies and especially AML continue to be a much more challenging setting for developing novel immunotherapies, which often have only modest clinical activity in the form of short-lived, transient responses and are complicated by frequent dose-limiting toxicities. Recent setbacks are the discontinuation of clinicals trials investigating the CD47 antibody magrolimab due to insufficient activity and increased risk of death, or the largely disappointing activity of immune checkpoint blockade in AML/myelodysplastic syndrome, with the exception of rare responses, such as in patients with posttransplant leukemia cutis relapse.
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Blood
TP53-Mutated Acute Myeloid Leukemia: How Can We Improve Outcomes?
Stahl M
Despite advances in the treatment paradigm of patients with acute myeloid leukemia (AML), TP53 mutated AML represents a molecular subgroup that has failed to improve with an overall survival around 6 months that is independent of age and fitness. Notably, there has been significant elucidation in understanding the biology of the disease and key advancements in the classification and prognostication of these patients. International collaborative efforts of novel clinical interventions are urgently needed to change the standard of care.
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Cell Stem Cell
A One-Way Street Recognition Approach to Mediate Allogeneic Immune Cell Therapies
Liu F, Romee R
CD54 and CD58 are adhesion proteins that mediate efficient immune synapse formation. Hammer et al. now show that the abrogation of these molecules in T and NK cells prevents their immune rejection while maintaining their effector function. These findings should significantly help advance our efforts to generate "off-the-shelf" allogeneic products.
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Journal of Clinical Oncology
Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study
Sands J
PURPOSE: The randomized, open-label, global phase III TROPION-Lung01 study compared the efficacy and safety of datopotamab deruxtecan (Dato-DXd) versus docetaxel in patients with pretreated advanced/metastatic non-small cell lung cancer (NSCLC).
METHODS: Patients received Dato-DXd 6 mg/kg or docetaxel 75 mg/m2 once every 3 weeks. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Objective response rate, duration of response, and safety were secondary end points.
RESULTS: In total, 299 and 305 patients were randomly assigned to receive Dato-DXd or docetaxel, respectively. The median PFS was 4.4 months (95% CI, 4.2 to 5.6) with Dato-DXd and 3.7 months (95% CI, 2.9 to 4.2) with docetaxel (hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.91]; P = .004). The median OS was 12.9 months (95% CI, 11.0 to 13.9) and 11.8 months (95% CI, 10.1 to 12.8), respectively (HR, 0.94 [95% CI, 0.78 to 1.14]; P = .530). In the prespecified nonsquamous histology subgroup, the median PFS was 5.5 versus 3.6 months (HR, 0.63 [95% CI, 0.51 to 0.79]) and the median OS was 14.6 versus 12.3 months (HR, 0.84 [95% CI, 0.68 to 1.05]). In the squamous histology subgroup, the median PFS was 2.8 versus 3.9 months (HR, 1.41 [95% CI, 0.95 to 2.08]) and the median OS was 7.6 versus 9.4 months (HR, 1.32 [95% CI, 0.91 to 1.92]). Grade ?3 treatment-related adverse events occurred in 25.6% and 42.1% of patients, and any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8.8% and 4.1% of patients, in the Dato-DXd and docetaxel groups, respectively.
CONCLUSION: Dato-DXd significantly improved PFS versus docetaxel in patients with advanced/metastatic NSCLC, driven by patients with nonsquamous histology. OS showed a numerical benefit but did not reach statistical significance. No unexpected safety signals were observed.
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Journal of Clinical Oncology
Hypofractionated Preoperative Radiation Should Not Yet Be Used as Standard of Care for Extremity and Truncal Soft Tissue Sarcoma
Baldini EH
Soft tissue sarcomas (STS) represent <1% of all cancers and occur anywhere in the body, with 75% arising in extremities and trunk. Landmark randomized trials for STS of extremities established the following: (1) combined limb-sparing surgery and radiation therapy (RT) is standard of care; (2) oncologic outcomes are similar with preoperative or postoperative RT, but toxicities differ. The American Society of Radiation Oncology, National Comprehensive Cancer Network, and European Society for Medical Oncology have endorsed (1) preference for preoperative RT over postoperative RT due to more favorable long-term toxicity profile and (2) conventional fractionation of 50 Gy in 25 fractions over 5 weeks as standard of care for preoperative RT for STS.
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JAMA Oncology
Heterogeneity of Residual Disease After Neoadjuvant Systemic Therapy in Breast Cancer: A Review
Tarantino P, Tolaney SM, Mittendorf EA
IMPORTANCE: Over the past 2 decades, systemic therapy for early-stage breast cancer has gradually moved from the adjuvant to the neoadjuvant setting. Administration of systemic therapy before surgery leads to potential improvements in surgical outcomes and allows for the assessment of the pathologic response to treatment. For patients with residual disease (RD), 3 adjuvant strategies have been shown to improve outcomes: (1) adjuvant trastuzumab emtansine for ERBB2-positive disease, (2) adjuvant capecitabine for triple-negative disease, and (3) adjuvant olaparib for patients with germline BRCA variants. Furthermore, studies are testing novel drugs in the postneoadjuvant setting. Given the potential to tailor adjuvant therapy based on the response to preoperative systemic therapy, recognizing the complexities of response to neoadjuvant therapy and moving beyond the binary paradigm of RD vs experiencing a pathologic complete response is becoming increasingly necessary.
OBSERVATIONS: Novel antibody-drug conjugates, anti-ERBB2 tyrosine kinase inhibitors, and immune checkpoint inhibitors are being evaluated as additional rescue options in phase 3 trials for patients with RD after neoadjuvant treatment. Concomitantly, the prognostic role of RD has been refined by the introduction of the residual cancer burden. In addition, the genomic landscape of RD has been found to be associated with long-term prognosis, as has the immune background of the disease evaluated via the presence of tumor-infiltrating lymphocytes. Lastly, the dynamics of circulating tumor DNA may allow for further improvement in prognostication by understanding which patients harbor detectable minimal RD.
CONCLUSIONS AND RELEVANCE: Escalating adjuvant treatment has led to meaningful survival improvements among patients with breast cancer and RD after neoadjuvant therapy. Uncovering the anatomic and biological intricacies of RD will allow for increased precision in postneoadjuvant treatments, moving beyond the binary paradigm of RD vs pathologic complete response, toward more tailored rescue strategies in the adjuvant setting.
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Nature
CDK5-Cyclin B1 Regulates Mitotic Fidelity
Zheng XF, Sarkar A, Syed A, Nguyen H, Tomasik B, Huang K, Li F, D'Andrea AD, Spektor A, Chowdhury D
CDK1 has been known to be the sole cyclin-dependent kinase (CDK) partner of cyclin B1 to drive mitotic progression1. Here we demonstrate that CDK5 is active during mitosis and is necessary for maintaining mitotic fidelity. CDK5 is an atypical CDK owing to its high expression in post-mitotic neurons and activation by non-cyclin proteins p35 and p392. Here, using independent chemical genetic approaches, we specifically abrogated CDK5 activity during mitosis, and observed mitotic defects, nuclear atypia and substantial alterations in the mitotic phosphoproteome. Notably, cyclin B1 is a mitotic co-factor of CDK5. Computational modelling, comparison with experimentally derived structures of CDK-cyclin complexes and validation with mutational analysis indicate that CDK5-cyclin B1 can form a functional complex. Disruption of the CDK5-cyclin B1 complex phenocopies CDK5 abrogation in mitosis. Together, our results demonstrate that cyclin B1 partners with both CDK5 and CDK1, and CDK5-cyclin B1 functions as a canonical CDK-cyclin complex to ensure mitotic fidelity.
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Nature Chemical Biology
Ubiquitin-Specific Proximity Labeling for the Identification of E3 Ligase Substrates
Huang HT, Lumpkin RJ, Tsai RW, Su S, Zhao X, Xiong Y, Chen J, Mageed N, Donovan KA, Fischer ES, Sellers WR
Protein ubiquitylation controls diverse processes within eukaryotic cells, including protein degradation, and is often dysregulated in disease. Moreover, small-molecule degraders that redirect ubiquitylation activities toward disease targets are an emerging and promising therapeutic class. Over 600 E3 ubiquitin ligases are expressed in humans, but their substrates remain largely elusive, necessitating the development of new methods for their discovery. Here we report the development of E3-substrate tagging by ubiquitin biotinylation (E-STUB), a ubiquitin-specific proximity labeling method that biotinylates ubiquitylated substrates in proximity to an E3 ligase of interest. E-STUB accurately identifies the direct ubiquitylated targets of protein degraders, including collateral targets and ubiquitylation events that do not lead to substrate degradation. It also detects known substrates of E3 ligase CRBN and VHL with high specificity. With the ability to elucidate proximal ubiquitylation events, E-STUB may facilitate the development of proximity-inducing therapeutics and act as a generalizable method for E3-substrate mapping.
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Nature Communications
Therapeutic Efficacy of Intracerebral Hematopoietic Stem Cell Gene Therapy in an Alzheimer's Disease Mouse Model
Montepeloso A, Kumar R, Ferro F, Cavalca E, Das S, Pellin D, Peviani M, Biffi A
The conditions supporting the generation of microglia-like cells in the central nervous system (CNS) after transplantation of hematopoietic stem/progenitor cells (HSPC) have been studied to advance the treatment of neurodegenerative disorders. Here, we explored the transplantation efficacy of different cell subsets and delivery routes with the goal of favoring the establishment of a stable and exclusive engraftment of HSPCs and their progeny in the CNS of female mice. In this setting, we show that the CNS environment drives the expansion, distribution and myeloid differentiation of the locally transplanted cells towards a microglia-like phenotype. Intra-CNS transplantation of HSPCs engineered to overexpress TREM2 decreased neuroinflammation, A? aggregation and improved memory in 5xFAD female mice. Our proof of concept study demonstrates the therapeutic potential of HSPC gene therapy for Alzheimer's disease.
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Nature Medicine
Trastuzumab Deruxtecan in HER2-Positive Advanced Breast Cancer with or without Brain Metastases: A Phase 3b/4 Trial
Lin NU
Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2+) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2+ mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n?=?263) and no BMs (n?=?241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4?mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ?3: 3%) of patients with BMs and 13% (grade ?3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2+ mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761.
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Blood Advances
Active Infection at the Time of CD34+ Selected Stem Cell Boost is Associated with Treatment Failure and Poor Overall Survival
Shapiro RM, Kim HT, Dulery R, Liney D, Garrity HM, Panaro K, Au C, Gervais C, Little JS, Ho VT, Cutler CS, Koreth J, Gooptu M, Antin JH, Kelkar AH, Romee R, Wu CJ, Ritz J, Soiffer RJ, Nikiforow S
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Blood Cancer Discovery
Tracking Rare Single Donor and Recipient Immune and Leukemia Cells After Allogeneic Hematopoietic Cell Transplantation Using Mitochondrial DNA Mutations
Penter L, Cieri N, Maurer K, Lyu H, Lu WS, Oliveira G, Gohil SH, Leshchiner I, Neuberg DS, Kim HT, Li S, Ritz J, Getz G, Garcia JS, Soiffer RJ, Livak KJ, Wu CJ
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Cancer Immunology Research
Blockade of IL1? and PD1 with Combination Chemotherapy Reduces Systemic Myeloid Suppression in Metastatic Pancreatic Cancer with Heterogeneous Effects in the Tumor
Dias Costa A, Cardot-Ruffino V, Rahma OE, Singh H, Abrams TA, Biller LH, Cleary JM, Enzinger P, Huffman BM, McCleary NJ, Perez KJ, Rubinson DA, Schlechter BL, Surana R, Yurgelun MB, Wang SJ, Remland J, Brais LK, Bollenrucher N, Chang E, Ali LR, Lenehan PJ, Lima C, Keheler CE, Sullivan KM, Dougan M, Wolpin BM, Nowak JA, Dougan SK
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Cell Metabolism
Development of a Functional Beige Fat Cell Line Uncovers Independent Subclasses of Cells Expressing UCP1 and the Futile Creatine Cycle
Vargas-Castillo A, Sun Y, Smythers AL, Grauvogel L, Dumesic PA, Emont MP, Tsai LT, Rosen ED, Zammit NW, Ordonez M, Chouchani ET, Gygi SP, Spiegelman BM
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Clinical Cancer Research
A Phase II Study of Atezolizumab, Pertuzumab, and High-Dose Trastuzumab for Central Nervous System Metastases in Patients with HER2-Positive Breast Cancer
Giordano A, Jin Q, Binboga Kurt B, Ren S, Li T, Leone JP, Mittendorf EA, Pereslete AM, Davis R, DiLullo M, Tayob N, Mayer EL, Winer EP, Tolaney SM, Lin NU
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Clinical Cancer Research
Detecting Small Cell Transformation in Patients with Advanced EGFR Mutant Lung Adenocarcinoma through Epigenomic cfDNA Profiling
El Zarif T, Meador CB, Seo JH, Davidsohn MP, Savignano H, Lakshminarayanan G, McClure HM, Canniff J, Fortunato B, Li R, Banwait MK, Semaan K, Eid M, Long H, Hung YP, Mahadevan NR, Barbie DA, Oser MG, Piotrowska Z, Choueiri TK, Baca SC, Hata AN, Freedman ML, Berchuck JE
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