|
Blood
Asciminib Plus Dasatinib and Prednisone for Philadelphia Chromosome-Positive Acute Leukemia
Luskin MR, Murakami MA, Keating J, Flamand Y, Winer ES, Garcia JS, Stahl M, Stone RM, Wadleigh M, Jaeckle SL, Hagopian E, Liegel J, McMasters M, DeAngelo DJ
Dasatinib is an effective treatment for Philadelphia chromosome-positive (Ph+) acute leukemia, but some patients develop resistance. Combination treatment with dasatinib and asciminib, an allosteric inhibitor of BCR::ABL1, may deepen responses and prevent the emergence of dasatinib-resistant clones. In this phase 1 study (NCT03595017), 24 adults with Ph+ acute lymphoblastic leukemia (ALL; n = 22; p190, n = 16; p210, n = 6) and chronic myeloid leukemia in lymphoid blast crisis (n = 2) were treated with escalating daily doses of asciminib in combination with dasatinib 140 mg daily plus prednisone 60 mg/m2 daily to determine the maximum tolerated dose. After a 28-day induction, dasatinib and asciminib were continued indefinitely or until hematopoietic stem cell transplant. The median age was 64.5 years (range, 33-85; 50% aged ?65 years). The recommended phase 2 dose of asciminib was 80 mg daily in combination with dasatinib and prednisone. The dose limiting toxicity at 160 mg daily was asymptomatic grade 3 pancreatic enzyme elevation without symptomatic pancreatitis. There were no vaso-occlusive events. Among patients with de novo ALL, the complete hematologic remission rates at days 28 and 84 were 84% and 100%, respectively. At day 84, 100% of patients achieved complete cytogenetic remission, 89% achieved measurable residual disease negativity (<0.01%) by multicolor flow cytometry, and 74% and 26% achieved BCR::ABL1 reverse transcription quantitative polymerase chain reaction <0.1% and <0.01%, respectively. Dual BCR::ABL1 inhibition with dasatinib and asciminib is safe with encouraging activity in patients with de novo Ph+ ALL. This trial was registered at www.clinicaltrials.gov as #NCT02081378.
|
|
Blood
Frontline Management of Mantle Cell Lymphoma
Ryan CE, Armand P, LaCasce AS
Despite many recent therapeutic advances, mantle cell lymphoma (MCL) remains a largely incurable disease. Treatments for patients with relapsed/refractory (R/R) disease are limited in number and in response durability. Therefore, improving the efficacy of frontline (1L) treatment, and specifically maximizing the duration of first remission, remains of critical importance to obtain favorable long-term outcomes. As 1L treatments become more effective, improving tolerability is also becoming an increasingly realistic goal. Targeted agents, which are now mainstays of treatment in R/R MCL, are establishing new, paradigm-changing roles in frontline treatment. Here, we review data supporting current standard-of-care approaches and explore 6 main areas of possible focus for advancement of 1L management: optimizing the chemoimmunotherapy (CIT) backbone, adding targeted agents to CIT, redefining the role of autologous stem cell transplantation, improving maintenance therapy, using targeted agent combinations with omission of CIT, and using measurable residual disease-guided therapy. We highlight several ongoing phase 3 trials that may soon impact frontline MCL management, and outline some areas of necessary investigation as the field continues to strive toward a cure for this disease.
|
|
Cancer Cell
Genomic Mediators of Acquired Resistance to Immunotherapy in Metastatic Melanoma
Schiantarelli J, Benamar M, Park J, Sax HE, Oliveira G, Bosma-Moody A, Liu D, Rodig S, Wu CJ, Hodi FS, Van Allen E, Haq R
Although some patients with metastatic melanoma experience durable responses to immune checkpoint inhibitors (ICIs), most exhibit intrinsic or acquired resistance to these therapies. Here, we compare somatic genomic profiles from matched pre-treatment and post-resistance tumor biopsies in patients (n = 25) with metastatic melanoma who exhibited heterogeneous ICI responses to nominate additional mediators of acquired resistance. We find that several acquired resistance tumors exhibit defects in B2M or JAK1/2, consistent with prior findings. We also discover resistance-associated mutations in SEC24C and SEC24D in 3 patients. SEC24 has an essential role in the trafficking of the dsDNA sensor STING and has been linked to interferonopathies. Melanoma cells engineered to express the SEC24C mutations observed in patients exhibit diminished STING signaling, including decreased type I interferon production, antigen presentation, and a reduced capacity to activate cytotoxic T cells. This study nominates a role for aberrant STING trafficking in acquired resistance to ICIs.
|
|
Cell Genomics
A Multi-Modal Transformer for Cell Type-Agnostic Regulatory Predictions
Javed N, Bernstein BE
Sequence-based deep learning models have emerged as powerful tools for deciphering the cis-regulatory grammar of the human genome but cannot generalize to unobserved cellular contexts. Here, we present EpiBERT, a multi-modal transformer that learns generalizable representations of genomic sequence and cell type-specific chromatin accessibility through a masked accessibility-based pre-training objective. Following pre-training, EpiBERT can be fine-tuned for gene expression prediction, achieving accuracy comparable to the sequence-only Enformer model, while also being able to generalize to unobserved cell states. The learned representations are interpretable and useful for predicting chromatin accessibility quantitative trait loci (caQTLs), regulatory motifs, and enhancer-gene links. Our work represents a step toward improving the generalization of sequence-based deep neural networks in regulatory genomics.
|
|
Cell Stem Cell
Gene Editing without Ex Vivo Culture Evades Genotoxicity in Human Hematopoietic Stem Cells
Zeng J, Nguyen MA, da Silva LF, Levesque S, Lin LY, Justus DG, Petri K, Clement K, Verma A, Neri NR, Rosanwo T, Mintzer E, Maitland SA, Cha HJ, Orkin SH, Williams DA, Pinello L, Joung JK, Pattanayak V, Manis JP, Pellin D, Brendel C, Wolfe SA, Bauer DE
Gene editing the BCL11A erythroid enhancer is a validated approach to fetal hemoglobin (HbF) induction for ?-hemoglobinopathy therapy, though heterogeneity in edit allele distribution and HbF response may impact its safety and efficacy. Here, we compare combined CRISPR-Cas9 editing of the BCL11A +58 and +55 enhancers with leading gene modification approaches under clinical investigation. Dual targeting of the BCL11A +58 and +55 enhancers with 3xNLS-SpCas9 and two single guide RNAs (sgRNAs) resulted in superior HbF induction, including in sickle cell disease (SCD) patient xenografts, attributable to simultaneous disruption of core half E-box/GATA motifs at both enhancers. Unintended on-target outcomes of double-strand break (DSB) repair in hematopoietic stem and progenitor cells (HSPCs), such as long deletions and centromere-distal chromosome fragment loss, are a byproduct of cellular proliferation stimulated by ex vivo culture. Editing quiescent HSPCs bypasses long deletion and micronuclei formation and preserves efficient on-target editing and engraftment function.
|
|
Gastroenterology
Taming Lynch Syndrome: The Remarkable Power of Prevention for One Family
Yurgelun MB
Up until the late twentieth century, familial adenomatous polyposis was thought to be the only form of inherited colorectal cancer (CRC) susceptibility. Familial CRC without polyposis was initially reported by Warthin in the early 1900s. Decades later, Lynch and Krush identified additional similar families and followed up the progeny of Warthin’s family, coining the term “cancer family syndrome,”2 and later “hereditary non-polyposis colorectal cancer” (HNPCC). Despite such reports, however, there remained considerable skepticism about the existence of HNPCC, with such familial CRC clustering often attributed to statistical chance or other causes, such as oncogenic viruses. The linkage of HNPCC to the microsatellite instability (MSI) mutational signature and defective DNA mismatch repair (MMR) function in 1993 however, quickly led to the discovery of 4 MMR genes, and germline pathogenic variants (PVs) which were confirmed to cause HNPCC now known as Lynch syndrome (LS).
|
|
JAMA
US Science in Peril
Walensky RP, Walensky LD
On January 22, 2025, the National Institutes of Health (NIH) came to a sudden standstill. Study sections were halted and agency communications muzzled, sparking alarm across the US scientific community. Study sections represent the steady flow of scientific progress and consist of panels of experts who convene 3 times yearly to critically review scientific proposals from the US’ budding and seasoned scientists alike. Its members review approximately 10 grants per session, with multiple experts assigned to each grant in an effort to maximize fairness and rigor. Preparing applications for submission takes months of painstaking work and the reviewers who study the applications, draft reviews, and complete a scoring rubric do so essentially pro bono (ie, ~$600 for weeks of preparatory review and several days of meeting, often including travel). For most of these scientists, whether writer or reviewer, the ultimate reward is not what is printed in green or wired to an institutional account, but rather the thrill of discovery and the satisfaction that comes with contributing to potentially lifesaving research.
|
|
Journal of Clinical Oncology
Anthracyclines in Early Breast Cancer: The Long Goodbye
Grinda T, Burstein HJ
For more than 50 years, through successive iterations of regimens incorporating alkylating agents, anthracyclines, and taxanes, adjuvant cytotoxic chemotherapy has improved the prognosis of patients with early breast cancer, reducing recurrence and cancer-related death. Remarkable progress in supportive care—especially antiemetics and growth factor support—has made treatment feasible and tolerable for a greater percentage of patients, although longer-term risks remain, including neuropathy, fatigue, and deconditioning. Anthracyclines in particular are persistently linked to rare instances of cardiac injury or myelodysplasia/acute myeloid leukemia (AML).
|
|
Journal of Clinical Oncology
Minimal Residual Disease-Based End Point for Accelerated Assessment of Clinical Trials in Multiple Myeloma: A Pooled Analysis of Individual Patient Data from Multiple Randomized Trials
Anderson KC, Munshi N
PURPOSE: Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease-negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM.
PATIENTS AND METHODS: Individual patient data from 20 randomized multicenter trials were collected. Eleven studies (4,773 patients) with sufficient data were analyzed to evaluate whether 9- or 12-month MRD-CR classified at a 10-5 threshold could be reasonably likely to predict the clinical benefit of new agents regarding PFS and OS. Global odds ratio (OR) was estimated using the bivariate Plackett Copula model. Supportive evaluation included correlations of the treatment effects on MRD-CR end points and PFS/OS, evaluated by both linear regression (R2weighted least squared) and Copula (R2Copula) models.
RESULTS: The analysis demonstrated that both 9- and 12-month MRD-CR strongly correlated with PFS at patient level in NDTE patients, NDTinE patients, and patients with RRMM. Global ORs ranged from 3.06 to 16.24, all with 95% CIs excluding 1.0. Encouraging trial-level correlations (R2, 0.61-0.70) were observed by pooling three populations and were stronger (R2, 0.67-0.78) in the ND population. Similar results were observed for OS.
CONCLUSION: Our findings provided the support for use of MRD-CR classified at a 10-5 threshold at either 9 or 12 months after starting of the treatment, as an intermediate end point to support accelerated approvals, in future trials in NDTE patients, NDTinE patients, and patients with RRMM.
|
|
Lancet Oncology
Landscape of Subsequent Therapies in Perioperative Immunotherapy Trials Across Multiple Cancer Types
Semaan K, Nawfal R, Choueiri TK
Over the past decade, immune checkpoint inhibitor (ICI) therapies have redefined the standard of care in many cancer types across stages and indications. Backed by large randomised controlled trials (RCTs) across several tumour types, perioperative ICI therapies have become an important addition to our treatment options. However, questions regarding the importance of subsequent treatment administered to trial patients in the control group (often placebo or surveillance) after recurrence quickly arose, leading to debates over trial design and application in real-world practice.
|
|
Nature
A Neoantigen Vaccine Generates Antitumour Immunity in Renal Cell Carcinoma
Braun DA, Chea V, McGregor BA, Blass E, Tu CR, Vanasse AP, Forman C, Forman J, Afeyan AB, Liu Y, Li S, Southard J, Chang SL, Hirsch MS, LeBoeuf NR, Olive O, Mehndiratta A, Greenslade H, Shetty K, Klaeger S, Sarkizova S, Mossanen M, Carulli I, Tarren A, Duke-Cohan J, Howard AA, Iorgulescu JB, Shim B, Simon JM, Signoretti S, Aster JC, Elagina L, Carr SA, Leshchiner I, Getz G, Gabriel S, Hacohen N, Oliveira G, Neuberg DS, Livak KJ, Shukla SA, Fritsch EF, Wu CJ, Keskin DB, Ott PA, Choueiri TK
Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1-6. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phase?I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage?III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2?months after surgery, none of the 9 participants enrolled in the study had a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T?cell immune responses against the PCV antigens, including to RCC driver mutations in VHL, PBRM1, BAP1, KDM5C and PIK3CA. Following vaccination, there was a durable expansion of peripheral T?cell clones. Moreover, T?cell reactivity against autologous tumours was detected in seven out of nine patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations and can induce antitumour immunity. These observations, in conjunction with the absence of recurrence in all nine vaccinated patients, highlights the promise of PCVs as effective adjuvant therapy in RCC.
|
|
Nature Communications
Single-Cell RNA Sequencing Defines Distinct Disease Subtypes and Reveals Hypo-Responsiveness to Interferon in Asymptomatic Waldenstrom's Macroglobulinemia
Sklavenitis-Pistofidis R, Konishi Y, Heilpern-Mallory D, Wu T, Tsakmaklis N, Aranha MP, Hunter ZR, Ali AK, Tsuji J, Haradhvala NJ, Lightbody ED, Towle K, Hevenor L, Romee R, Briercheck EL, Smith EL, Treon SP, Getz G, Ghobrial IM
Waldenstrom's Macroglobulinemia (WM) is an IgM-secreting bone marrow (BM) lymphoma that is preceded by an asymptomatic state (AWM). To dissect tumor-intrinsic and immune mechanisms of progression, we perform single-cell RNA-sequencing on 294,206 BM tumor and immune cells from 30 patients with AWM/WM, 26 patients with Smoldering Myeloma, and 23 healthy donors. Despite their early stage, patients with AWM present extensive immune dysregulation, including in normal B cells, with disease-specific immune hallmarks. Patient T and NK cells show systemic hypo-responsiveness to interferon, which improves with interferon administration and may represent a therapeutic vulnerability. MYD88-mutant tumors show transcriptional heterogeneity, which can be distilled in a molecular classification, including a DUSP22/CD9-positive subtype, and progression signatures which differentiate IgM MGUS from overt WM and can help advance WM research and clinical practice.
|
|
New England Journal of Medicine
Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors
Chan JA, Meyerhardt JA
BACKGROUND: Treatment options for patients with advanced neuroendocrine tumors are limited. The efficacy of cabozantinib in the treatment of previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumors is unclear.
METHODS: We enrolled two independent cohorts of patients - those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors - who had received peptide receptor radionuclide therapy or targeted therapy or both. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib at a dose of 60 mg daily or placebo. The primary end point was progression-free survival as assessed by blinded independent central review. Key secondary end points included objective response, overall survival, and safety.
RESULTS: In the cohort of 203 patients with extrapancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 8.4 months, as compared with 3.9 months with placebo (stratified hazard ratio for progression or death, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P<0.001). In the cohort of 95 patients with pancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 13.8 months, as compared with 4.4 months with placebo (stratified hazard ratio, 0.23; 95% CI, 0.12 to 0.42; P<0.001). The incidence of confirmed objective response with cabozantinib was 5% and 19% among patients with extrapancreatic and pancreatic neuroendocrine tumors, respectively, as compared with 0% with placebo. Grade 3 or higher adverse events were noted in 62 to 65% of the patients treated with cabozantinib, as compared with 23 to 27% of the patients who received placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events.
CONCLUSIONS: Cabozantinib, as compared with placebo, significantly improved progression-free survival in patients with previously treated, progressive advanced extrapancreatic or pancreatic neuroendocrine tumors. Adverse events were consistent with the known safety profile of cabozantinib. (Funded by the National Cancer Institute and others; CABINET ClinicalTrials.gov number, NCT03375320.).
|
|
Blood Advances
A Real-World Comparison of Commercial-Use Axicabtagene Ciloleucel and Lisocabtagene Maraleucel in Large B-Cell Lymphoma
Looka A, Qualls DA, Matthews D, Redd RA, Sakellis C, Duffy C, Dela Cruz J, Saucier A, Armand P, Crombie JL, Fisher DC, Jacobsen ED, Kim AI, LaCasce AS, Merryman RW, Parry EM, Jacobson CA
|
|
|
|
Blood Advances
Venetoclax Plus Low-Intensity Chemotherapy for Adults with Acute Lymphoblastic Leukemia
Luskin MR, Shimony S, Keating J, Winer ES, Garcia JS, Stone RM, Flamand Y, Stevenson K, Ryan J, Letai A, DeAngelo DJ
|
|
|
|
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
|
|
Cancer
Outcomes and Treatment Patterns for Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the Surveillance, Epidemiology, and End Results Database, 2010-2019
Waks AG, Tarantino P, Chen EL, Freedman RA, Lin NU, Tayob N, Tolaney SM, Leone JP
|
|
|
|
Cancer Research Communications
Functional Profiling of p53 and RB Cell Cycle Regulatory Proficiency Suggests Mechanism-Driven Molecular Stratification in Endometrial Carcinoma
Yang Z, Mogre S, Jun H, Ghosh Chaudhary S, Bhattarai UR, Ho Sui SJ, Matulonis UA, Lazo S, Shetty A, Cameron A, Nguyen QD, Hill SJ
|
|
Clinical Cancer Research
A Phase II Study of Abemaciclib for Patients with Retinoblastoma-Positive, Triple-Negative Metastatic Breast Cancer
Jovanovi? B, Chu X, Hughes M, Erick TK, Russo D, DiLullo M, Wrabel E, Jeselsohn R, Lin NU, Tayob N, Mittendorf E, Schnitt S, Tolaney SM
|
|
JNCI Cancer Spectrum
The Use of Large Language Models to Enhance Cancer Clinical Trial Educational Materials
Chen S, Goddla V, Gallifant J, Doyle P, Novack C, Dillon-Martin M, Perkins T, Sharon E, Lehmann LS, Kozono D, Bitterman DS
|
|
Journal of Hematology Oncology
First-in-Human Evaluation of Memory-Like NK Cells with an IL-15 Super-Agonist and CTLA-4 Blockade in Advanced Head and Neck Cancer
Shapiro RM, Sheffer M, Booker MA, Tolstorukov MY, Birch GC, Sade-Feldman M, Fang J, Li S, Lu W, Ansuinelli M, Dulery R, Tarannum M, Baginska J, Penter L, Abdulhamid YZ, Kaplan IE, Khanhlinh D, Uppaluri R, Redd RA, Nikiforow S, Koreth J, Ritz J, Wu CJ, Soiffer RJ, Hanna GJ, Romee R
|
|
Nature Metabolism
Oncogenic TFE3 Fusions Drive OXPHOS and Confer Metabolic Vulnerabilities in Translocation Renal Cell Carcinoma
Li J, Huang K, Thakur M, McBride F, Sadagopan A, Gallant DS, Khanna P, Laimon YN, Li B, Mohanna R, Ge M, Weiss CN, Achom M, Xu Q, Matar S, Lee GM, Huang K, Wu CL, Cornejo KM, Choueiri TK, Ryback BA, Signoretti S, Bar-Peled L, Viswanathan SR
|
|
Nature Methods
The Dynamics of Hematopoiesis Over the Human Lifespan
Li H, Ezike J, Frenis K, Tanaka-Yano M, Tarantino G, Whangbo J, Morris V, Wang D, Chen AF, Bianchi G, Daley GQ, Garg S, Liu D, Rowe RG
|
|
Neuro-Oncology Practice
Glioma Resource Outreach with Support: A Program to Identify and Initiate Supportive Care Interventions for Unmet Needs Among Adult Lower-Grade Glioma Patients
Garcia Fox R, Chukwueke UN, Sannes T, Miran D, Chiu D, Bagley C, Holmes EG, Peirce B, Beroukhim R, Youssef G, McFaline-Figueroa JR, Aquilanti E, Quant Lee E, Nayak L, Wen PY, Gonzalez Castro LN, Reardon DA
|
|
Oncogene
Editorial Expression of Concern: Activation of NF-?B and Upregulation of Intracellular Anti-Apoptotic Proteins Via the IGF-1/Akt Signaling in Human Multiple Myeloma Cells: Therapeutic Implications
Mitsiades CS, Mitsiades N, Poulaki V, Schlossman R, Akiyama M, Chauhan D, Hideshima T, Treon SP, Munshi NC, Richardson PG, Anderson KC
|
|
|
|
