tbuckley/cabot-search huggingface dataset:
Preliminary results of a phase 1b study of fruquintinib plus sintilimab in advanced colorectal cancer.
Authors: Ye Guo, Weijie Zhang, Jieer Ying, Yanqiao Zhang, Yueyin Pan, Wensheng Qiu, Weiguo Su, Panfeng Tan, Hongyan Yin, Yan Wang, Yang Luo, Hui Zhou, Jin Li
Journal: Journal of Clinical Oncology (2021)

2514 Background: To explore the safety and synergistic anti-tumor effect of fruquintinib (a VEGFR inhibitor) in combination with sintilimab (an anti-PD-1 Ab) in patients (pts) with advanced colorectal cancer (CRC) and other solid tumors. Methods: This is an ongoing phase Ib/II, multicenter, two-stage study. Pts with variety cancer types, including CRC, were enrolled and is continuously enrolling in the study. For this interim analysis, all pts were analyzed for safety whereas only CRC pts were analyzed for efficacy. MMR status were analyzed for all enrolled CRC pts. Stage 1 was classical “3+3” dose escalation with pts assigned to one of the following 4 cohorts, fruquintinib taken orally at 3mg (Cohort A, 3 weeks on/ 1 week off), 4mg (Cohort B, 3 weeks on/ 1 week off), 5mg-intermittent (Cohort C, 2 weeks on/ 1 week off) or 3mg-continuous (Cohort E, once daily), while sintilimab was given at 200mg intravenously with Q4W in Cohort A and Cohort B whereas Q3W in Cohort C and Cohort E. DLT was observed for 28 days. Stage 2 was dose expansion with pts receiving 5mg-intermittent or 3mg-continuous fruquintinib plus sintilimab (200mg, Q3W). The primary endpoints were safety and tolerability and secondary endpoint was objective response rate (ORR). Results: As of Jan 5, 2021, 44 CRC pts which failed to at least 2 previous lines of therapy containing fluoropyrimidine, oxaliplatin or irinotecan were enrolled. They received either 5mg-intermittent or 3mg-continous dosage (n = 22, each), the ORR was 22.7% (10/44, 95% CI: 11.5-37.8%) with 27.3% (6/22, 95% CI: 10.7-50.2%) in 5mg-intermittent group and 18.2% (4/22, 95% CI: 5.2-40.3%) in 3mg-continuous group. With a median follow-up time of 8.3 (range: 0-9.6) months, the K-M estimated median PFS was 6.8 (95% CI:5.6-NA) months and 4.3 (95% CI:3.5-NA) months for 5mg-intermittent group and 3mg-continuous group, respectively. Overall, 60 pts were enrolled for safety analysis, including 23 in stage1 and 37 (only CRC) in stage 2. In stage 1, all pts experienced TEAEs, 52.2% of which were ≥ grade 3. The most frequently reported TEAEs were TSH increasing (73.9%), fecal occult blood positive (56.5%), and Palmar-plantar erythrodysaesthesia syndrome (PPES) (56.5%). SAEs occurred in 8 (34.8%) pts and no treatment-related death was reported. One patient in Cohort B reported manageable DLT. In stage 2, all pts experienced TEAEs, 18 (48.6%) pts experienced ≥ grade 3 TEAEs with 6 (31.6%) in 5mg-intermittent group and 12 (66.7%) in 3mg-continuous group. The most common TEAEs were proteinuria (45.9%) and TSH increasing (37.8%). TEAEs leading to either fruquintinib or sintilimab discontinuation occurred in 3 (5%) pts each. Conclusions: Fruquintinib plus sintilimab showed promising efficacy and favorable safety profile in advanced CRC. Clinical trial information: NCT03903705.
Combination olaparib and durvalumab for patients with recurrent IDH-mutated gliomas.
Authors: Ronald Ramos, Seth Andrew Climans, Ashley Adile, Pegah Ghiassi, Stephanie Baker, Madeline J. Phillips, Gelareh Zadeh, Eric Xueyu Chen, Warren P. Mason
Journal: Journal of Clinical Oncology (2021)

e14026 Background: Isocitrate dehydrogenase (IDH) mutations are frequently observed in low grade gliomas and secondary glioblastoma. Mutant IDH enzymes aberrantly convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG). Accumulation of 2HG inhibits αKG-dependent dioxygenases, many of which are involved in epigenetic regulation. This can lead to cellular dedifferentiation and tumor formation. IDH-mutated cancer cells exhibit defective homologous recombination repair, providing the rationale for investigating poly (adenosine 5’-diphophate-ribose) polymerase (PARP) inhibitors in these tumors. Blockade of programmed cell death ligand 1 (PD‐L1) re‐sensitizes PARP inhibitor treated cancer cells to T‐cell killing. We report the preliminary results of the glioma arm of a clinical trial of a PARP inhibitor, olaparib plus PD-L1 inhibitor, durvalumab, for IDH-mutated solid cancer. Methods: This is a single arm phase II basket study (NCT03991832). Patients with IDH-mutated solid tumors are divided into three cohorts; A: glioma; B: cholangiocarcinoma; C: all other solid tumors. Major eligibility criteria include IDH mutation by immunohistochemistry or sequencing, progressive disease with maximum two prior systemic therapies, Eastern Cooperative Oncology Group performance status (ECOG) 0 –1 and adequate organ function. Patients were excluded if they had received prior PARP inhibitors or anti-PD-1/PD-L1 antibodies. Patients were treated with olaparib 300 mg orally twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Each cycle was 4 weeks. Tumor response was evaluated by MRI after every 2 cycles of study treatments using response evaluation criteria in solid tumors (RECIST). Results: As of Jan 2021, 9 patients were enrolled in Arm A, 7 men and 2 women. The median age was 42 years. Eight patients had IDH1 mutations and 1 had an IDH2 mutation. There were two patients with 1p/19q codeletion. Two patients had grade 2 tumors, four had grade 3, and three had grade 4 tumors. Median time since tumor diagnosis was 7 years. Objective response was seen in 1 patient with an IDH-mutated glioblastoma who remains on study treatments after 8 cycles. Six patients (67%) had tumor progression after two cycles. Two patients had stable disease as per RECIST but had clinical deterioration and did not continue the combined treatment. Common treatment emergent adverse events were all grade 1: fatigue (8 patients), nausea (6), abdominal pain (3), anemia (3), thrombocytopenia (3), and diarrhea (2). Median progression free survival was 2.5 months (range 1.9–8 months). Updated analysis and correlative studies will be presented at the meeting. Conclusions: Combination treatment with olaparib and durvalumab for patients with IDH-mutated glioma is well tolerated but appears to lack adequate antitumor activity. Clinical trial information: NCT03991832.
Metabolic alterations mediated by STAT3 promotes drug persistence in CML
Authors: Sweta B. Patel, Travis Nemkov, Davide Stefanoni, Gloria A. Benavides, Mahmoud A. Bassal, Brittany L. Crown, Victoria R. Matkins, Virginia Camacho, Valeriya Kuznetsova, Ashley T. Hoang, Danielle E. Tenen, Samuel L. Wolock, Jihye Park, Li Ying, Zongliang Yue, Jake Y. Chen, Henry Yang, Daniel G. Tenen, Paul Brent Ferrell, Rui Lu, Victor Darley-Usmar, Angelo D’Alessandro, Ravi Bhatia, Robert S. Welner
Journal: Leukemia (2021)

Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs.
Abstract 12534: Racial Differences in Utilization, Trends, and Prognostic Impact of Guideline-Directed Medical Therapy for HFrEF in the Community: The Atherosclerosis Risk in Communities (ARIC) Surveillance Study
Authors: Lena Mathews, Ning Ding, Laura R Loehr, Jung-im Shin, Naresh M Punjabi, Alain G Bertoni, Deidra C Crews, Wayne D Rosamond, Chiadi E Ndumele, Kunihiro Matsushita, Patricia Chang
Journal: Circulation (2019)

Introduction: Racial differences in utilization, trends, and prognostic impact of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) have not been sy...
Construction and validation of an eight-gene risk prediction model for stage II-IIIA lung adenocarcinoma.
Authors: Jianchun Duan, Hua Bai, Yiting Sun, Fei Gai, Shenya Tian, Wenfang Xu
Journal: Journal of Clinical Oncology (2021)

e20553 Background: Clinical characters cannot precisely evaluate long-term survival of patients with resectable lung adenocarcinoma. Genomics studies of lung adenocarcinoma (LUAD) have advanced our understanding of LUAD's biology. Thus, genomics-based robust models predicting survival outcome for patients with operatable LUAD needs to be investigated. Here, we aimed to identify new gene signatures to construct a risk prediction model via integrating Omics data from The Cancer Genome Atlas (TCGA) to better evaluate the long-term clinical outcome of LUAD patients. Methods: A cohort of one hundred and eighty-nine stage II-IIIA lung adenocarcinoma cases receiving tumor resection were screened out and downloaded from TCGA database. Tumor samples without survival information and genes with low or no expression were removed. Genes associated with cancer and immune were further narrowed down using a Master Panel Gene Set (Amoydx). Lasso-Cox regression analysis was used to screen gene-survival outcome, and then a risk prediction model was established. LUAD cases were divided into high-risk or low-risk groups as per the scores, to assess differential expressed genes and pathways. Results: A total of 8 most survival outcome related genes (CLEC7A, PAX5, XCR1, KRT7, PLCG1, DKK1, CLEC10A, IKZF3) were identified after Lasso-Cox regression analysis and used for model construction. The overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) from the subgroups within the high- and low-risk groups were assessed and showed significant prolonged in low-risk group, the hazard ratio (HR) of OS was 2.72 (95%CI: 2.04-3.61, P = 5.91 e-12 ) in high-risk group. Hierarchical clustering analysis, gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) revealed that genes involved in immune responses were significantly suppressed in high-risk group, while as genes involved in antioxidative metabolism were activated, which gave us a hint that immune-metabolism interaction might play a vital role in determining the distal survival outcome of LUAD. Conclusions: Our risk prediction model enables precise evaluation of long-term survival for patients with LUAD. Further, it provides a novel and comprehensive understanding of biological impacts on LUAD prognosis, which offers new insights for future development of precise diagnostic and therapeutic approaches.[Table: see text]
Consistent performance of highly multiplexed RNA fusion detection with low RNA input and limit of detection.
Authors: David Debruyne, Chenyu Li, Julia Spencer, Vidushi Kapoor, Lily Y. Liu, Lucie Lee, Rounak Feigelman, Grayson Burdon, Jeffrey Liu, Guoying Liu, Zhitong Liu
Journal: Journal of Clinical Oncology (2021)

e15029 Background: Gene fusions are usually caused by chromosomal rearrangements and frequently associated with various cancers. Detection of fusion mutations is an important part of cancer management, and are usually detected in RNA purified from biopsies of fresh tissue or FFPE sections. However, the amount of RNA from these samples is usually limited. We developed a new, PCR-based fusion detection method, which allows detection of unknown and novel fusion mutations. We demonstrate its consistent performance across various RNA inputs, and sequencing depths, in terms of technical performance and limit of detection. Methods: A multiplex PCR RNA fusion panel was designed to cover known RNA fusion targets and unknown fusion targets for target enrichment via single primer multiplex PCR. SeraSeq fusion Reference RNA was used to evaluate the limit of detection of the method. The amplicons were about 110 bp on average to allow for target amplification from challenging fragmented samples such as FFPE RNA. After reverse transcription, the panel was used in a multiplex PCR to amplify the targets, and a final PCR was used to add sequencing adapters and sample indexes. The resulting libraries were sequenced on Illumina sequencers. The data was analyzed for the detection of known fusion variants across varying initial inputs of targets, as well as the performance in terms of mapping and on-target rates, as well as the presence of human ribosomal RNA. Results: We found that the fragmented RNA length had little effect on the performance of the libraries. The required numbers of PCR cycles were optimized based on testing with various amounts of starting RNA input material. We observe a linear relationship between the library yields and RNA input amounts from 10 to 50ng, which had R1 mapping rates above 95% and 98%, respectively. We report the detection of all twelve fusion variants, which are targeted by our panel and present in the Seraseq Fusion RNA Mix v4 reference standard, and which are covered with an average sequencing depth of 0.2M reads, or 3600 reads/amplicon, across all assays. Even at inputs as low as 3 ng, all 12 fusions were typically detected. In general, the results for individual fusions among the different replicates were concordant, with limited observed variance in reads across some fusion junctions between assays and replicates. Over 90% of the reads supported the fusion calls from all inputs (ranging from 1.6 to 50 ng). Over 97% of the reads supported the fusion calls between 12 and 50 ng. Conclusions: A multi-lab validation confirmed the above results, and were also comparable when using an additional distinct CleanPlex fusion panel. To conclude, our CleanPlex fusion technology allows for reliable and simultaneous detection of 12 designed clinically relevant RNA fusions even at low input amounts.
Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2
Authors: Giulia Pellizzari, Olivier Martinez, Silvia Crescioli, Robert Page, Ashley Di Meo, Silvia Mele, Giulia Chiaruttini, Jan Hoinka, Ihor Batruch, Ioannis Prassas, Melanie Grandits, Jacobo López-Abente, Eva Bugallo-Blanco, Malcolm Ward, Heather J Bax, Elise French, Anthony Cheung, Sara Lombardi, Mariangela Figini, Katie E Lacy, Eleftherios P Diamandis, Debra H Josephs, James Spicer, Sophie Papa, Sophia N Karagiannis
Journal: Journal for ImmunoTherapy of Cancer (2021)

Cancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies. Employing mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy. We identified the target of the SF-25 clone as the tumor-associated antigen SLC3A2, a cell surface protein with key roles in cancer metabolism. We generated IgE monoclonal antibody, and CAR T cell immunotherapies each recognizing SLC3A2. In concordance with preclinical and, more recently, clinical findings with the first-in-class IgE antibody MOv18 (recognizing the tumor-associated antigen Folate Receptor alpha), SF-25 IgE potentiated Fc-mediated effector functions against cancer cells in vitro and restricted human tumor xenograft growth in mice engrafted with human effector cells. The antibody did not trigger basophil activation in cancer patient blood ex vivo, suggesting failure to induce type I hypersensitivity, and supporting safe therapeutic administration. SLC3A2-specific CAR T cells demonstrated cytotoxicity against tumor cells, stimulated interferon-γ and interleukin-2 production in vitro. In vivo SLC3A2-specific CAR T cells significantly increased overall survival and reduced growth of subcutaneous PC3-LN3-luciferase xenografts. No weight loss, manifestations of cytokine release syndrome or graft-versus-host disease, were detected. These findings identify efficacious and potentially safe tumor-targeting of SLC3A2 with novel immune-activating antibody and genetically modified cell therapies.
Targeting the Microtubule EB1-CLASP2 Complex Modulates Na <sub>V</sub> 1.5 at Intercalated Discs
Authors: Gerard A. Marchal, Mariam Jouni, David Y. Chiang, Marta Pérez-Hernández, Svitlana Podliesna, Nuo Yu, Simona Casini, Franck Potet, Christiaan C. Veerman, Mischa Klerk, Elisabeth M. Lodder, Isabella Mengarelli, Kaomei Guan, Carlos G. Vanoye, Eli Rothenberg, Flavien Charpentier, Richard Redon, Alfred L. George, Arie O. Verkerk, Connie R. Bezzina, Calum A. MacRae, Paul W. Burridge, Mario Delmar, Niels Galjart, Vincent Portero, Carol Ann Remme
Journal: Circulation Research (2021)

[Figure: see text].
Enhanced pathologic tumor response with two cycles of neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC).
Authors: Ravindra Uppaluri, Rebecca Chernock, Mena Mansour, Ryan Jackson, Jason Rich, Patrik Pipkorn, Randal C Paniello, Sidharth Puram, Jose P. Zevallos, Donald J. Annino, Laura A. Goguen, Luc Morris, Robert I. Haddad, Glenn J. Hanna, Peter John Oppelt, Lara Dunn, Jessica C. Ley, Dorina Kallogjeri, Ann Marie Egloff, Douglas Adkins
Journal: Journal of Clinical Oncology (2021)

6008 Background: We reported that one cycle of neoadjuvant pembrolizumab induced pathologic tumor response in &gt;10% (pTR-any) and in &gt;50% (pTR-2) of the resection bed in 44% and 22% of patients (pts) with surgically resectable HPV-negative, Stage III/IV HNSCC ( Clin Cancer Res 2020). We hypothesized that two cycles of neoadjuvant pembrolizumab would induce pTR-2 in 50% of pts. Increasing the pathologic response rate may favorably impact clinical outcomes. Methods: Multi-institutional phase 2 trial where pts with locally advanced, HPV-negative HNSCC received two cycles of pembrolizumab (200 mg), given 42 and 21 days prior to surgery. Resected tumor was analyzed by two independent pathologists for pTR (tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris) in the resection bed (primary tumor and/or lymph nodes). Additional definitions: pTR-1 (&gt;10-49%) and major pathologic response ( &gt; 90%). The primary endpoint was pTR-2. A sample size of 26 pts was needed to detect a significantly higher pTR-2 rate of 50%, with 80% power using a one-sided alpha level of 0.05. Pts were followed for serious adverse events (AEs) for 30 days after surgery and for AEs of clinical interest for 90 days following the last dose of pembrolizumab. Pts underwent baseline blood collection and tumor biopsies to match with blood and surgical specimens obtained post-pembrolizumab. Planned correlatives included PD-L1 expression, immune function, and molecular signatures of activation in the pre- and post-treatment blood and tumor tissue. Results: Characteristics of 29 enrolled and treated pts were median age 62 (30-82) yrs, smoking history 62% (18 pts); clinical stage T 2 (n = 6), T 3 (n = 5), T 4 (n = 18) and N 0/1 (n = 17), N 2 (n = 12). All treated patients received two cycles of neoadjuvant pembrolizumab, which was tolerated well with only one (3%) grade 3 AE (rash) and no grade 4 AEs. The primary endpoint was evaluable in 25 pts, and not evaluable in 4 pts (one pt withdrew before surgery and in three pts, pTR review was pending). pTR-2 occurred in 44% (11 of 25 pts), and 4 (16%) of these pts had a major pathologic response including 1 (4%) pathologic CR at the primary site. Conclusions: Two (vs one) cycles of neoadjuvant pembrolizumab resulted in a two-fold increase in the frequency of pTR-2 (44% vs 22%). These data imply that the frequency of pTR to neoadjuvant pembrolizumab can be improved by increasing the number of cycles and the treatment interval. Clinical trial information: NCT02296684.
A systematic review of post-transplant lymphoproliferative disorder after liver transplant.
Authors: Mobeen Zaka Haider, Zarlakhta Zamani, Hasan Mehmood Mirza, Hafsa Shahid, Muhammad Taqi, Yousra Khalid, Mohsin Sheraz Mughal, Fnu Kiran, Deepak Kumar, Ahsan Wahab, Muhammad Salman Faisal, Muhammad Umair Mushtaq, Faiz Anwer
Journal: Journal of Clinical Oncology (2021)

e19045 Background: Post-transplant lymphoproliferative disorder (PTLD) is a complication after liver transplantation. This study aims to explore the association of PTLD with the immunosuppression, types of PTLD, clinical presentation, and outcomes. Methods: Following the PRISMA guideline, we searched the literature on PubMed, Cochrane, Embase, and clinicaltrials.gov. 1741 articles were screened and 22 studies were included. Results: Data includes 22,235 total patients who underwent a liver transplant, and 449 (2.0%) patients who developed PTLD were studied. Of the 394 patients where gender was reported, 226 were male and 168 were female. Post-transplant EBV status was positive for 63/115 (56%). 11 studies showed that the median time from transplant to the development of PTLD was 33.4 months. Among the histological types of PTLD, the monomorphic B-cell was the most common type with 127/235 (54%) cases, followed by early lesions 25/235, polymorphic 24/235, Hodgkin lymphoma 8/235, and monomorphic T-cell type 7/235. Treatment of PTLD involved reduction or cessation of the immunosuppressive drugs along with chemotherapy surgery and radiotherapy. Mortality data from 13 studies showed 68/259 (31.3%) patients died either due to PTLD or its complication. Conclusions: PTLD is rare but associated with high mortality after liver transplantation. EBV seropositivity is associated with PTLD in the majority of cases. Monomorphic PTLD is the most common type of PTLD after liver transplantation with DLBCL being the most common subtype. Abdominal symptoms and fever are among the most common symptoms. PTLD after Liver transplant a review of studies. [Table: see text]