tbuckley/cabot-search huggingface dataset:
Phase 1 dose escalation and cohort expansion study evaluating safety, PK, PD and clinical activity of STC-15, a METTL-3 inhibitor, in patients with advanced malignancies.
Authors: Justin C Moser, Kyriakos P. Papadopoulos, Jordi Rodon Ahnert, Yaara Ofir-Rosenfeld, Josefin-Beate Holz
Journal: Journal of Clinical Oncology (2024)

2586 Background: RNA modifications are involved in cancer initiation and progression. The most abundant modification of mRNA is m6A generated by METTL3. Inhibition of METTL3 causes double-stranded RNA formation and activation of cellular T1 IFN response. IFN signaling induces IFN-stimulated gene families i.e. IFIT and OAS, characteristic of an anti-viral response, and secretion of cytokines and chemokines. STC-15, a first in class small molecule inhibitor of METTL3 developed by Storm Therapeutics, demonstrated in pre-clinical models, activation of IFN signaling and remodeling of the TME towards pro-inflammatory state. We report the dose escalation results from a FIH trial in patients with advanced malignancies. Methods: This is a multi-center, open-label, dose escalation study. STC-15 oral capsules are administered daily or t.i.w. in 21-d treatment cycles. Dose escalation follows 3+3 modified Fibonacci regimen. Primary objectives are safety and PK. Secondary objectives are preliminary evidence of anticancer activity and RP2D. Exploratory objectives are PD (i.e. target engagement and immune activation biomarkers) and correlation of primary pharmacology with observed clinical efficacy. Results: As of 02/01/2024, 31 patients enrolled across 4 dose levels and 5 cohorts: 60mg QD (6 pats), 60mg t.i.w. (3 pats), 100mg t.i.w. (14 pats), 160 mg t.i.w. (5 pats) and 200mg t.i.w. (3 pats). PK profile supports t.i.w. dosing. A total of 169 AEs were observed with 45 AEs attributed to STC-15 treatment. AEs were manageable, mostly hematology (thrombocytopenia 31%; 4% Grade 3), skin (pruritis, rash 14% G1/2) and GI (N/V and diarrhea 14% G1/2). 12 SAEs occurred; 1 pt (60mg QD) had DLT with G3 pneumonitis. Of 14 patients with at least 1 on-treatment scan, DCR is 78% with 2 confirmed PR ongoing in angiosarcoma (60mg, 32 weeks) and IO-refractory NSCLC (100mg, 33 weeks) and 9 SD. An average of 63% reduction in m6A on mRNA in peripheral blood within the first 24h post dosing was observed in 60mg cohorts, confirming target engagement. Whole blood Nanostring and pathway analysis of gene expression confirms upregulation of innate immune pathways (i.e. T1,2 IFN activation and anti-viral responses) as early as 8h after first dose and throughout the treatment cycle. Updated PK/PD and clinical data will be presented. Conclusions: Treatment with STC-15 is well tolerated across pharmacologically active dose range with encouraging signs of clinical activity. Early biomarker data provide proof of mechanism in target engagement, strong activation of innate immune responses and correlation of pharmacological activity with clinical response. The study is ongoing and expansion cohorts are underway to further evaluate PK/PD, safety and clinical efficacy at optimized pharmacologically active doses. Clinical trial information: NCT05584111 .
Phase 1 LITESPARK-001 study of belzutifan in advanced solid tumors: Results of the glioblastoma cohort.
Authors: Roy E. Strowd, Macarena Ines De La Fuente, Todd Michael Bauer, Kyriakos P. Papadopoulos, Ke Chen, Rodolfo F. Perini, Yanfang Liu, David F. McDermott
Journal: Journal of Clinical Oncology (2024)

2054 Background: Patients with progressive/recurrent glioblastoma (GBM) have very poor prognosis, and novel treatments are urgently needed. Hypoxia is a prominent feature of the tumor microenvironment in GBM and has been implicated as a potential mechanism of resistance to radiation therapy, which is a key part of standard-of-care treatment for GBM. HIF-2α has been suggested as a key therapeutic target because it plays a role in stabilizing the hypoxic environment in GBM tumors. Belzutifan, a first-in-class HIF-2α, has shown efficacy in advanced renal cell carcinoma and in von Hippel-Lindau disease–related renal cell carcinoma, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas. The phase 1 LITESPARK-001 trial (NCT02974738) was designed to evaluate belzutifan across solid tumors. Here, we report results from the GBM expansion cohort of LITESPARK-001. Methods: Patients enrolled in the GBM cohort had histologically confirmed, IDH wild type GBM that is first recurrent following radiation therapy and temozolomide according to the Response Assessment in Neuro-Oncology (RANO) criteria and had a measurable contrast-enhancing lesion by MRI imaging and a Karnofsky performance scale score ≥60%. Patients received belzutifan 120 mg by mouth twice daily. End points for this cohort included objective response rate (ORR), clinical benefit rate (CBR, CR + PR + SD of any duration), and progression-free survival (PFS) per RANO criteria by investigator assessment and safety. Results: Overall, 25 patients were enrolled in the GBM cohort. Median age was 63 years (range, 35-75), and most patients were male (n = 15; 60%). Median follow-up was of 1.9 months (range, 0.7-5.1). ORR was 0% (95% CI, 0.0-13.7) and CBR was 8% (95% CI, 1.0-26.0). Median PFS was 1.4 months (95% CI, 1.1-1.8). All patients (100%) experienced ≥1 adverse event and 15 (60%) experienced a grade 3-5 adverse event. The most common adverse events were anemia (n = 16 [64%]), fatigue (n = 13 [52%]), headache (n = 8 [32%]), muscular weakness (n = 8 [32%]). Two patients (8%) died from adverse events (both disease progression). No deaths were considered related to treatment. Conclusions: Antitumor activity was not observed with belzutifan for patients with GBM who received prior radiation therapy and temozolomide. The safety profile was similar to previous studies with belzutifan. Further efforts are warranted to identify therapies for patients with glioblastoma to improve outcomes. Clinical trial information: NCT02974738 .
Organ-specific immune-related adverse events and survival in patients with cancer with immune checkpoint inhibitors.
Authors: Jun Wang, Xinyue Han, Yingcui Chen, Hong Xie, Yuekai Zhang, Yu Cui, Yaping Guan
Journal: Journal of Clinical Oncology (2024)

12124 Background: Immunotherapy with immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). This study was designed to assess whether the occurrence of irAEs or different irAE characteristics correlates with survival outcomes in advanced cancer patients treated with ICIs. Methods: This cohort study included a panel of patients with advanced cancer who received ICI therapy at a single institute. Kaplan‒Meier curves were generated to describe progression-free survival (PFS) and overall survival (OS) in patients with irAEs or specific irAE characteristics. Results: A total of 238 patients were enrolled, and 83 (34.9%) patients developed at least one irAE. The irAE development was associated with prolonged OS (not reached vs 17.8 months, HR: 0.48, p &lt; 0.001), PFS (8.7 vs 4.8 months, HR: 0.63, p = 0.003), and an improved objective response rate (24.1% vs 10.3%, p = 0.005). However, irAE characteristics, including severity, number of organs or systems affected, and timing of onset, were not associated with OS. Furthermore, we observed that only skin and endocrine toxicities independently protected against OS and PFS. Based on the results from organ-specific irAEs, the first development of skin or endocrine toxicities as protective irAEs rather than other irAEs was an independent indicator for predicting OS (HR: 0.24, p &lt; 0.001) and PFS (HR: 0.43, p&lt; 0.001). A prognostic irAE score based on organ-specific irAEs was developed to show the effect of total protective irAEs on patient outcomes. Conclusions: Not all irAEs are associated with prolonged survival. Identification of organ-specific irAEs but not other irAE characteristics is useful for stratifying patients who actually respond to and benefit from ICIs across different cancer types.
Direct oral anticoagulant versus low molecular weight heparin for venous thromboembolism in patients receiving immune checkpoint inhibitors.
Authors: Cho Han Chiang, Yu-Cheng Chang, Zhiting Tang, Xin Ya See, Kuan-Yu Chi, Yu Chang, Cho Hung Chiang, Jingyi Gong, Lauren Mary Curtis, Tomas G. Neilan
Journal: Journal of Clinical Oncology (2024)

12127 Background: The two most common therapies for the treatment of cancer-associated venous thromboembolism (VTE) are low molecular weight heparin (LMWHs) and direct oral anticoagulants (DOACs). However, there is a paucity of data on the optimal anticoagulation strategy specifically among patients receiving immune checkpoint inhibitors (ICIs). Therefore, we aimed to evaluate the comparable safety and efficacy of DOACs versus LMWHs in the treatment of VTE among patients receiving ICIs. Methods: We conducted a retrospective, propensity score-matched cohort study using the TriNetX Analytics Network, which contains de-identified data from over 120 healthcare institutions and 250 million patients. We included adult cancer patients who have received ICI therapy including nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, ipilimumab, dostarlimab and who also received a diagnosis of VTE. Patients treated with DOACs were matched in a 1:1 ratio to patients treated with LMWHs based on the variables: age, sex, metastatic disease, cancer therapy, underlying comorbidities, Khorana score, and history of intracranial and gastrointestinal bleeding. The primary outcome was the occurrence of a new VTE, a composite of pulmonary embolism (PE) and deep venous thrombosis (DVT). The safety outcomes included all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding within 2 years following the start of anticoagulation therapy. Results: We matched 4608 ICI-treated patients on a DOAC to 4608 ICI-treated patients on a LMWH. In a Cox proportional hazard analysis, patients receiving DOACs or LMWH had a similar risk of a subsequent VTE event (Hazard ratio (HR), 1.13 [95% CI: 0.84-1.50]). When comparing different types of VTEs, the DOAC group was associated with a lower risk of PE (HR, 0.72 [95% CI: 0.54-0.96]) and a similar risk of DVT (HR, 0.87 [95% CI: 0.70-1.09]) compared to LMWHs. Furthermore, DOACs were associated with a lower risk of intracranial hemorrhage and all-cause mortality. There were no detectable differences in the risk of gastrointestinal bleeding between the two groups. Conclusions: DOACs were associated with a similar risk for subsequent VTE events but a lower risk of intracranial bleeding as well as an improvement in mortality compared to LMWHs among ICI-treated patients with a diagnosis of VTE. Prospective trials are needed to validate these findings. [Table: see text]
Association between hyperglycemia and the development of chemotherapy-induced peripheral neuropathy among patients with breast cancer.
Authors: Miriam Pearl Klahr, Khadija Faheem, Rohit R. Raghunathan, Dawn L. Hershman, Melissa Kate Accordino
Journal: Journal of Clinical Oncology (2024)

12125 Background: Poorly controlled diabetes is a predictor of chemotherapy induced peripheral neuropathy (CIPN), and hyperglycemia (HG) may mediate CIPN risk. The association between CIPN and HG is not well studied. Our objective was to evaluate the association between HG and CIPN development. Methods: The CONTRoL trial was a phase IIB randomized adaptive sequential selection trial that evaluated cryotherapy vs. compression vs. placebo to prevent CIPN in patients with Stage I-III breast cancer during taxane therapy. Patients completed the Functional Assessment of Cancer Therapy Neurotoxicity (FACT-NTX) survey at baseline, week-12, and week-24. CIPN development was defined as ≥ 5-point increase in FACT-NTX from baseline. We included patients who completed FACT-NTX at baseline and week-12. HG (any glucose ≥ 140 mmol/L) was assessed via chart review of random glucose laboratory results collected from time of taxane initiation through week-24. Patients were divided into two groups based on CIPN development (yes/no). For each group we calculated the proportion of patients with HG, and mean glucose at baseline, week-12 and week-24 with values obtained +/-7 days of specified timeframe; 95% confidence intervals were constructed. Results: Sixty-three patients participated in the CONTRoL study and 59 patients were included in this analysis. All 59 patients had ≥1 recorded glucose value during the 24-week period (n= 410 total values), with a median of 6 values (range 1-12) per patient. When comparing patients who did and did not develop CIPN, 29.4% vs. 20.0% were Black (p=0.72), 41.2% vs. 52.0% were Hispanic/Latino (p=0.69), 17.6% vs. 8.0% had diabetes (p=0.49) and 64.7% vs. 48.0% received docetaxel (p=0.31). There were higher rates of HG, 47.1% vs. 36.0%, in patients who developed CIPN vs. those who did not (p=0.56). Mean glucose was higher in patients who developed CIPN compared to those who did not at all timepoints (Table). Conclusions: In this secondary analysis, we found that almost half of patients with CIPN had HG compared to about a third of patients without CIPN, and that patients with CIPN had higher mean glucose at all timepoints compared to patients without CIPN. Due to the small sample size, differences were not statistically significant, but notable trends were observed. Further research is needed to confirm this finding and evaluate the impact of glucose lowering interventions on preventing the development of CIPN. Clinical trial information: NCT03873272 . [Table: see text]
Phase I/II trial of gabapentin plus intranasal ketamine for the prevention and treatment of pain in patients undergoing radiotherapy for head and neck cancer.
Authors: Natalie A Lockney, Derek Smith, Lindsay Mundy, Phyllis Kilpatrick, Taylor Butler, Zachary Kohutek, Anthony Cmelak, Sean All, Ryan Whitaker, Barbara A. Murphy
Journal: Journal of Clinical Oncology (2024)

12123 Background: Pain is ubiquitous in head and neck cancer (HNC) patients undergoing radiotherapy (RT) with up to 40% developing chronic pain. Gabapentin initiated concurrently with RT reduces pain intensity, opioid use, and dysphagia; however, gabapentin may not fully control pain, and dose escalation may be limited by toxicity. Novel non-opioid analgesic combinations administered concurrent with RT may address these limitations. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. The NMDA receptor modulates mood and pain and is involved in central sensitization. Blocking the NMDA receptor may decrease the development and severity of neuropathic pain and decrease/prevent central sensitization. In combination with other analgesics, ketamine may enhance acute and chronic pain control at lower doses thus avoiding dose-limited toxicities. We report results from the dose-finding phase I study of gabapentin plus intranasal (NAS) ketamine in HNC patients undergoing RT; phase II is ongoing. Methods: Eligibility: locally advanced non-metastatic HNC planned for primary or adjuvant RT with or without concurrent chemotherapy. Primary objective of phase I was to determine the maximum tolerated dose (MTD) or maximum planned dose (MPD) for NAS ketamine combined with gabapentin (300mg TID). Planned dose levels (DL) were DL1: 10 mg TID, DL2: 20 mg TID, DL3: 30 mg TID and DL 4: 40 mg TID. A phase II expansion was planned at the MTD/MPD to confirm safety and feasibility. Results: Eleven patients were enrolled during phase I, which has been completed. No dose limiting toxicities (DLTs) were noted at DL1, DL2 or DL3. Two DLTs were reported at DL4: grade 2 dizziness and grade 2 sedation. The MTD was ketamine 30 mg NAS TID. Six patients are enrolled on the phase II trial at the MTD which is ongoing. Conclusions: The MTD of NAS ketamine was 30mg TID combined with gabapentin 300mg. The Phase II expansion is ongoing. Clinical trial information: NCT05156060 .
A novel NIR-II albumin-escaping probe for cerebral arteries and perfusion imaging in stroke mice model
Authors: Ying-Ying Sun, Hong-Jing Zhu, Yijing Du, Shoujun Zhu, Sheng-Yu Zhou, Shu-Yan Pang, Yang Qu, Jia-Cheng Liu, Shuang-Yin Lei, Yi Yang, Zhen-Ni Guo
Journal: Biomaterials (2024)
Innate-like T cells in liver disease
Authors: Albert Ying-Po Yang, Kilian Wistuba-Hamprecht, Tim F. Greten, Benjamin Ruf
Journal: Trends in Immunology (2024)

Mammalian innate-like T cells (ILTCs), including mucosal-associated invariant T (MAIT), natural killer T (NKT), and γδ T cells, are abundant tissue-resident lymphocytes that have recently emerged as orchestrators of hepatic inflammation, tissue repair, and immune homeostasis. This review explores the involvement of different ILTC subsets in liver diseases. We explore the mechanisms underlying the pro- and anti-inflammatory effector functions of ILTCs in a context-dependent manner. We highlight latest findings regarding the dynamic interplay between ILTC functional subsets and other immune and parenchymal cells which may inform candidate immunomodulatory strategies to achieve improved clinical outcomes in liver diseases. We present new insights into how distinct gene expression programs in hepatic ILTCs are induced, maintained, and reprogrammed in a context- and disease stage-dependent manner.
Author Correction: Vaccination induces broadly neutralizing antibody precursors to HIV gp41
Authors: Torben Schiffner, Ivy Phung, Rashmi Ray, Adriana Irimia, Ming Tian, Olivia Swanson, Jeong Hyun Lee, Chang-Chun D. Lee, Ester Marina-Zárate, So Yeon Cho, Jiachen Huang, Gabriel Ozorowski, Patrick D. Skog, Andreia M. Serra, Kimmo Rantalainen, Joel D. Allen, Sabyasachi Baboo, Oscar L. Rodriguez, Sunny Himansu, Jianfu Zhou, Jonathan Hurtado, Claudia T. Flynn, Katherine McKenney, Colin Havenar-Daughton, Swati Saha, Kaitlyn Shields, Steven Schultze, Melissa L. Smith, Chi-Hui Liang, Laura Toy, Simone Pecetta, Ying-Cing Lin, Jordan R. Willis, Fabian Sesterhenn, Daniel W. Kulp, Xiaozhen Hu, Christopher A. Cottrell, Xiaoya Zhou, Jennifer Ruiz, Xuesong Wang, Usha Nair, Kathrin H. Kirsch, Hwei-Ling Cheng, Jillian Davis, Oleksandr Kalyuzhniy, Alessia Liguori, Jolene K. Diedrich, Julia T. Ngo, Vanessa Lewis, Nicole Phelps, Ryan D. Tingle, Skye Spencer, Erik Georgeson, Yumiko Adachi, Michael Kubitz, Saman Eskandarzadeh, Marc A. Elsliger, Rama R. Amara, Elise Landais, Bryan Briney, Dennis R. Burton, Diane G. Carnathan, Guido Silvestri, Corey T. Watson, John R. Yates, James C. Paulson, Max Crispin, Gevorg Grigoryan, Andrew B. Ward, Devin Sok, Frederick W. Alt, Ian A. Wilson, Facundo D. Batista, Shane Crotty, William R. Schief
Journal: Nature Immunology (2024)
Implementing an EU pull incentive for antimicrobial innovation and access: blueprint for action
Authors: Michael Anderson, Adrian Towse, Kevin Outterson, Elias Mossialos
Journal: The Lancet Microbe (2024)

In June, 2023, the Council of the EU published a recommendation that the European Commission should contribute to the design and governance of an EU cross-country pull incentive to stimulate antimicrobial innovation and access. In this Personal View, we discuss six key considerations to support the implementation of the new pull incentive-ie, the size of the potential pull incentive and possible contributions of the member states, design of the incentive model, interplay of the new pull incentive with the proposed revisions of the EU pharmaceutical legislation, roles and responsibilities of both the EU and member states, balance between pull and push incentives, and global cooperation and responsibility. As the involvement of the member states with the EU pull incentive will be voluntary, member states should have confidence that the processes used to identify eligible antimicrobials, negotiate terms and conditions, and oversee access agreements are transparent, inclusive, and methodologically robust.
Challenging the Paradigm of “BCG-unresponsive” Bladder Cancer: Does Additional Bacillus Calmette-Guérin Have an Effect?
Authors: Amanda A. Myers, Wei Shen Tan, Valentina Grajales, Hyunsoo Hwang, Kelly K. Bree, Neema Navai, Byron H. Lee, Colin P.N. Dinney, Ashish M. Kamat
Journal: European Urology (2024)
Deep Amplicon Sequencing Reveals Culture Selection of <i>Mycobacterium Tuberculosis</i> by Clinical Samples
Authors: Jiuxin Qu, Wanfei Liu, Shuyan Chen, Chi Wu, Wenjie Lai, Rui Qin, Feidi Ye, Yuanchun Li, Liang Fu, Guofang Deng, Lei Liu, Qiang Lin, Peng Cui
Journal: Genomics Proteomics & Bioinformatics (2024)

Abstract The commonly-used drug susceptibility testing (DST) relies on bacterial culture and faces shortcomings such as long turnaround time and clone/subclone selection. We developed a targeted deep amplification sequencing (DAS) method directly applied to clinical specimens. In this DAS panel, we examined 941 drug-resistant mutations associated with 20 anti-tuberculosis drugs with an initial amount of 4 pg DNA and reduced clinical testing time from 20 days to two days. A prospective study was conducted using 115 clinical specimens mainly with Xpert® Mycobacterium tuberculosis/rifampicin (Xpert MTB/RIF) assay positive to evaluate drug-resistant mutation detection. DAS was performed on culture-free specimens, while culture-dependent isolates were used for phenotypic DST, DAS, and whole-genome sequencing (WGS). For in silico molecular DST, our result based on DAS panel revealed the similar accuracy to three published reports based on WGS. For 82 isolates, application of DAS showed better sensitivity (93.03% vs. 92.16%), specificity (96.10% vs. 95.02%), and accuracy (91.33% vs. 90.62%) than Mykrobe software using WGS. Compared to culture-dependent WGS, culture-free DAS provides a full picture of sequence variation at population level, exhibiting in detail the gain-and-loss variants caused by bacterial culture. Our study performs a systematic verification of the advantages of DAS in clinical applications and comprehensively illustrates the discrepancy in Mycobacterium tuberculosis before and after culture.
Still high risk? A review of translocation t(14;16) in multiple myeloma
Authors: Hira Mian, Martin Kaiser, Rafael Fonseca
Journal: American Journal of Hematology (2024)

Abstract Multiple myeloma (MM) is a heterogeneous and complex disease, both in mutational biology as well as in the clinical presentation of patients. While tailored and biomarker‐targeted therapy remains the direct goal for patient‐centric management, existing therapies in MM remain largely uniform. Translocation t(14;16) is a rare primary genetic event found in less than 5% of patients with newly diagnosed MM. Here, we present an overview of the biology of t(14;16), epidemiology, clinical presentation, prognostic impact, and discuss the future clinical and therapeutic strategies for targeting this rare yet high‐risk group in MM to optimize patient outcomes.