tbuckley/cabot-search huggingface dataset:
<i>NFKBIA</i> deletions reshape the epigenome antithetical to the <i>IDH</i> mutation and indication of prognosis in diffuse gliomas.
Authors: Markus Bredel, Lluis Espinosa, Stephanie L. Pugh, Arnab Chakravarti
Journal: Journal of Clinical Oncology (2024)

2083 Background: Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. The NFKBIA gene at 14q13.2 encodes IkBa, a protein that regulates the activity of NF-kB in the cytoplasm. Evidence that, in chromatin, nuclear NFKBIA dynamically interacts with histones H2A and H4 to regulate polycomb-dependent transcriptional repression and, thus, stem cell maturation and lineage specification and our characterization of NFKBIA as a tumor suppressor in glioblastoma prompted our investigation of the relationship of NFKBIA deletions to other genetic markers, alterations in the methylome, and the clinical course of gliomas. Methods: We analyzed the genetic profiles of 2,343 WHO grade 2 to 4 diffuse gliomas in multiple clinically well-characterized patient populations, including national randomized phase III consortium trial RTOG 9802, to determine whether incorporation of NFKBIA deletions could enhance the prognostic value of current molecular descriptions. Results: We demonstrate that haploinsufficient deletions of NFKBIA display distinct patterns of occurrence in relation to other genetic markers, including driver mutations IDH, TERT, ATRX, and PTEN, 1p19q codeletion, and CDKN2A/B deletion, and are disproportionally present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation. The methylome changes facilitated through NFKBIA deletions engender a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas and are highly enriched for neural stem cell and neurogenesis genes bearing repressive H3K27 marks. Our findings imply that the NFKBIA deletion in adult gliomas and the H3K27M mutation in pediatric diffuse midline gliomas define aggressive disease subtypes that may share an epigenetic state reflecting a common PRC2 loss-of-function phenotype antipodal to the quasi PRC2 gain-of-function phenotype of IDH mutant gliomas and their favorable clinical course. Lower-grade gliomas harboring NFKBIA deletions behave much like high-grade gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wildtype tumors. A sparse, easily interpretable, and externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas, incorporating NFKBIA deletion and current best-established genetic and clinicopathologic factors, confirms that NFKBIA deletions predict comparatively brief survival. Conclusions: NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into clinical models predicting the disease fate of diffuse gliomas.
Open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-175 in human leukocyte antigen-a*02:01-positive adult subjects with unresectable, advanced and/or metastatic solid tumors that are positive for the TP53 R175H mutation.
Authors: Carlos Roberto Becerra, Mark M. Awad, J. Randolph Hecht, Andrew Scott Paulson, Jennifer Lee, Gabi Palluconi, Jaquelin Dalton, Anuradha Patel, Ying Yan, Arianne Perez, Sunny Xie, Sarah Cohen, Marwan Fakih
Journal: Journal of Clinical Oncology (2024)

e14514 Background: The TP53 tumor suppressor gene is the most commonly mutated gene across all cancer types, and TP53 R175H is the most common recurrent mutation across indications, identified in 6.7% of patients with breast cancer, 6% of patients withs colorectal cancer, and 4.2% of patients with pancreatic cancer. No therapy is approved for treatment directly targeting TP53 R175H. NT-175 is an armored autologous T-cell product expressing an HLA-A*02:01-restricted TCR recognizing TP53 R175H with disruption of the endogenous TCR and the transforming growth factor beta receptor type 2 (TGFBR2) genes. Methods: This first-in-human phase I, open label study will assess the safety and preliminary anti-tumor activity, identify the maximum tolerated dose (MTD), and evaluate the persistence, and functional capacity of NT-175 in subjects with advanced, recurrent unresectable/metastatic solid tumors refractory to treatment options. The study will enroll approximately 24 subjects harboring TP53 R175H and HLA-A*02:01. Enrolled patients will undergo leukapheresis from which CD4 and CD8 T cells will be enriched and activated ex vivo. The endogenous TCR α and β chain gene are knocked out utilizing clustered Regularly Interspaced Short Palindromic repeats (CRISPR-Cas9) and the TCR encoding an HLA-A*02:01-restricted TCR specific to the TP53 R175H mutation is inserted in the TCR α locus. Additionally, the T cells are edited to disrupt the gene encoding the TGFBR2 to reduce the immunosuppressive effect of TGF-β in the tumor microenvironment. Subjects will undergo lymphodepletion chemotherapy with fludarabine and cyclophosphamide followed by a single infusion of NT-175 and subcutaneous recombinant IL-2 administration for up to 8 days. Dose escalation will occur across 3 ascending dose levels following the BOIN design. Subjects will be monitored for dose-limiting toxicities for 28 days after NT-175 infusion. Tumor response will be assessed by RECISTv1.1 criteria. All subjects will be followed for up to 15 years. Primary endpoints include safety, dose limited toxicities, MTD determination, and recommended Phase II dose. Secondary endpoints include preliminary efficacy measures. Translational analysis will evaluate potential biomarkers for insights into mechanism of action, response prediction, or resistance mechanisms. The study was activated in March 2023 and is open to accrual; 5 patients have been enrolled as of 4 Jan 2024.
Gender disparity in chimeric antigen receptor T-cell therapy utilization and outcomes in the United States.
Authors: Divya Solipuram, Kathan Mehta, Sudeep Kumar Siddappa Malleshappa
Journal: Journal of Clinical Oncology (2024)

2556 Background: Chimeric antigen receptor T-cell [CART] therapy has marked a new era in the treatment of relapsed/refractory hematological malignancies since its approval in 2017. Racial disparity was studies previously but not gender. Current study aimed to evaluate gender disparity in CART therapy utilization and outcomes. Methods: This cross sectional study was done using National Inpatient Sample [NIS], the largest database available in the US. Inpatient admissions of adults who received CART therapy for various indications during year 2020 were included. Results: A total of 6915 patients were admitted to hospital for CART therapy in 2020 with an overall inpatient mortality rate of 1%. Mean age of the patients was 57yr. Majority were White [64%], with a higher median household income, admitted to urban and large sized hospitals and predominantly covered by Medicare or private insurance [~80%]. Study population was divided into males and females and outcomes were compared. Females were significantly younger with lower Charlson comorbidity index and higher utilization of CART therapy [81% vs 19%] compared to males. Females had 86% lesser odds of mortality compared to males (Odds Ratio [OR] 0.14; 95% confidence interval [CI] 0.04-0.47; p value 0.001). Females had significantly lesser hospitalization charges [mean decrease $471,193; p value 0.000] and length of stay [mean decrease 8 days; p value 0.000] compared to males after adjusting for confounders. Racial differences in outcome were compared after multiple imputation was used to correct for 4% missing data in the race category in NIS 2020. There was no statistically significant difference in mortality, length of stay or hospitalization charges between Whites, Blacks and Hispanic races similar to previous studies. Conclusions: Eligibility criteria for CART therapy includes patients with good performance status and organ function with less comorbidities. Our study found that females were younger, healthier and therefore qualified better for CART therapy compared to males. Hence they had significantly higher utilization of CART therapy. In addition, among the population receiving CART therapy, females had better outcomes compared to males in terms of mortality, length of stay and hospitalization charges. In general, males have higher incidence and mortality with poorer outcomes in most hematological malignancies where CART therapy is a treatment option. Measures at modifying and improvising CART therapy to cater to more male subjects will not only reduce gender disparity but also improve overall survival and reduce disease burden. [Table: see text]
Intracellular retention of TCRαβ/CD3 to generate novel allogeneic CAR-T cells targeting CLL1 for treating acute myelocytic leukemia.
Authors: Jun Li, Kaichun Liu, Guanggui Xu, Shanshan Chen, Yinhang Zhang
Journal: Journal of Clinical Oncology (2024)

e14532 Background: The prognosis of patients with R/R AML is poor and treatment remains challenging. Human C-type lectin-like molecule 1(CLL1) is a type II transmembrane glycoprotein that is highly expressed on AML but is absent on normal HSCs. Clinical studies have shown that autologous CLL-1 is a novel and promising target for the treatment of AML. But autologous CAR-T therapy has been complicated by long production time, high-cost and risks of manufacturing failure, and allogeneic CAR-T cells can overcome these hurdles. Methods: A novel non-gene-editing allogeneic CAR-T platform was developed on the base of intracellular retention of membrane proteins, and named ThisCART (This = TCR and/or HLA-I intracellular sequestered). CLL1-directed ThisCART cells are readily produced with a single lentiviral vector, encoding both a CLL1-targeting CAR and an anti-CD3 single chain antibody with the KDEL peptide fused to its C-termini. The surface expression of CAR and TCRαβ/CD3 was measured by flow cytometer. Specific tumor cytotoxicity was evaluated both in vitro and in vivo. Furthermore, the safety of donor derived ThisCART cells were tested in a xenogeneic GvHD model. Results: The manufacturing platform of CLL1 ThisCART was able to achieve over 150-folds of ex vivo CAR-T expansion in all batches, with the purity of products (CAR-positive/TCRαβ-negative) above 99%. In preclinical models, CLL1 ThisCART did not induce GvHD, and exhibited superior antitumor function compared to benchmark (WO2017091615A) and conventional CLL1 CAR-T cells. CLL1 ThisCART cells were readily produced to a quantity and quality supporting clinical investigation. Conclusions: CLL1 ThisCART cells based on intracellular retention of TCRαβ/CD3 complex demonstrated superior CLL1-dependent cytotoxicity and no xenogeneic GvHD in murine models. With streamlined single-vector-based production, enhanced CAR signaling and potent cytotoxicity and favored preclinical safety profile, CLL1 ThisCART warrant clinical investigation.
Analytical and clinical validation of a personalized, tumor-informed circulating tumor DNA assay for minimal residual disease detection.
Authors: Zuoquan Yang, Yanqing Zhou, Yaru Chen, Jiaman Teng, Heng An, Shaochen Cheng, Mingyan Xu, Shifu Chen
Journal: Journal of Clinical Oncology (2024)

e14545 Background: The detection of minimal residual disease (MRD) through circulating tumor DNA (ctDNA) analysis provides an advanced molecular method for early identification of surgical patients at high risk of recurrence. In this study, we present the development of mClear, a personalized, tumor-informed next-generation sequencing (NGS) assay for MRD detection. Furthermore, we report the analytical and clinical validation processes conducted to evaluate the performance of the MRD assay. Methods: mClear is designed to assess MRD in patients with solid tumors. Whole exome sequencing (WES) was performed on tumor tissues and matched peripheral blood samples to detect somatic variants comprehensively. Personalized MRD assays were carefully designed by selecting up to 40 prioritized variants, including single nucleotide variants (SNVs), small insertions and deletions (InDels), and fusions while ensuring coverage of 21 additional key driver genes. For analytical validation, we utilized a pan-cancer MRD ctDNA quality control product (LDT-999, LDT Bioscience), characterized by known variant allele frequency (VAF) gradients of 0%, 0.005%, 0.05%, and 0.5%, confirmed through droplet digital PCR (ddPCR). We conducted 18 replicate tests at VAF gradients of 0.5% and 0.05%, 23 replicates at the 0.005% VAF gradient, and 16 replicates at the 0% VAF gradient. For clinical validation, preoperative and postoperative blood samples from a cohort of 264 pan-cancer patients were analyzed. ctDNA collected for MRD detection underwent ultra-deep next-generation sequencing (100,000× average depth of coverage). The library preparation process commenced with an input of 30ng DNA. Results: At VAF gradients of 0.5% and 0.05%, the assay achieved an excellent sensitivity of 100%, and at VAF gradients of 0.005% and 0%, it demonstrated a sensitivity of 95.7% and a specificity of 100%. Preoperative ctDNA was detected in 86.7% (72/83) of the pan-cancer patients with 71.4% (5/7), 90.9% (10/11), 85.5% (47/55), and 100.0% (10/10) in pathological stage (pStage)I, pStage II, pStage III, and pStage IV, respectively. In the pan-cancer cohort, the positive rate of longitudinal MRD was 35.7% (75/210) with 17.8% (21/118), 50.0% (13/26), 55.1% (27/49), and 82.4% (14/17) in pStage I, II, III, and IV, respectively. In four patients who relapsed, MRD detection during surveillance preceded radiological recurrence by a lead time of 1-8 months. Conclusions: Our personalized MRD assay demonstrated excellent analytical sensitivity and specificity with a limit of detection (LoD) of 0.005% VAF at the sample level. Furthermore, it displayed high clinical sensitivity for the detection of ctDNA in the pan-cancer cohort, highlighting its potential for monitoring of recurrence.
Pembrolizumab-induced myocarditis: A systematic review of case reports.
Authors: Walaa Hasan, Athar Eysa, Darshita Chauhan, Murad El-daraysah, Ahmed Ezzelden
Journal: Journal of Clinical Oncology (2024)

e14605 Background: Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized cancer therapy but are associated with immune-related adverse events (irAEs), including myocarditis, which can have serious clinical consequences. This systematic review aims to comprehensively analyze case reports to better understand pembrolizumab-induced myocarditis. Methods: Using keywords of "pembrolizumab" or "Keytruda" and "myocarditis" in the PubMed/Medline, ScienceDirect and clinicaltrials.gov databases and manual searches on Google Scholar, we reviewed all cases reported up to the year 2023. In total, 296 studies received primary screening. Duplicated articles and those meeting the exclusion criteria (not myocarditis, not human, not English, trials done in vitro, combination immunotherapies) were excluded. Review articles, retrospective studies, systematic reviews, and meta-analyses were also excluded. Finally, 45 studies matching the inclusion criteria were included (total of 46 patients). Data on patient demographics, clinical presentation, diagnostic criteria, management strategies, and outcomes were extracted and analyzed. Results: In the included 46 patients, the mean age was 65.5 years, with a slight male predominance (56.5%). Predominant cancer types included lung cancer (30.4%), thymoma (15.2%), melanoma (13.0%), and genitourinary cancers (13.0%). 45.7% of patients developed myocarditis after their first cycle of Pembrolizumab while 41.3% developed myocarditis after two cycles. 47.8% of patients presented with dyspnea, 23.9% with fatigue, 10.9% with chest pain, while 13% of the patients were asymptomatic and were subsequently diagnosed with myocarditis while presenting with other immune-related adverse events. Troponin levels were assessed in 45 individuals, with only 2.2% (one patient) having normal levels. ECG changes included ST segment elevation in 21.7%, conduction abnormalities (RBBB 15.2%, LBBB 6.5%, AV block 26.1%, and one unspecified conduction abnormality) in 50%, and arrhythmias in 37% of cases. Treatment included steroids for all, with varying outcomes. Four patients each received one of the following treatments: batacept, ruxolitinib, alemtuzumab, and methotrexate. All four of these patients showed improvement. Two patients received infliximab (4.3%) and both of them died. Outcomes revealed 34.8% mortality, 63.0% improvement, and 2.2% deterioration, including one sudden cardiac death 35 days post-discharge. Conclusions: Pembrolizumab-induced myocarditis is a rare but potentially life-threatening irAE. This systematic review provides a comprehensive overview of the clinical characteristics, diagnostic challenges, treatment approaches, and outcomes of this condition. Further research is needed to elucidate the underlying mechanisms and identify risk factors for pembrolizumab-induced myocarditis, enabling early detection and prevention strategies.
Advancing drug development by leveraging microdissection for proteogenomic analysis of histological sections.
Authors: Donald Joseph Johann, Ikjae Jae Shin, Michael Tangrea, Michael Emmert-Buck
Journal: Journal of Clinical Oncology (2024)

e14660 Background: Combining laser capture microdissection (LCM) with proteogenomics in cancer research offers a targeted way to way to explore the intricate interactions between the tumor microenvironment and tumor cells proper. For immuno-oncology (IO) research, this is especially important, since improvements in the predictability of patient response to IO-based drugs is greatly needed. An improved understanding of the spatial relationships involving tumor cells, stromal cells, blood supply and immune cell interactions may help to inform drug development and improve the indicators of success for IO-based drug regimens. Methods: From fresh frozen tissue, LCM is used to isolate and obtain distinct histological cell types. Nucleic acids and proteins are extracted from captured cells for in-depth multi-modality molecular profiling assays. This includes multiple genomic modalities and a customized solution-based mass spectrometry proteomics approach for samples or specimens with a limited amount of tissue. Results: Optimizing the analysis of minute tissue quantities from LCM captured cells is challenging. Following the isolation of nucleic acids, DNA sequencing can be performed for the discovery and analysis of actionable mutations, copy number variation, and methylation profiles. RNA-seq may be performed for gene expression. Regarding genomic-based studies, commercial kits are often utilized for these steps due to their general availability, rapid innovation, and the robust performance of these products. However, this kit-based adaptive approach is not true for proteomics. There remains a need for highly sensitive proteomic methods targeting small-sized samples. Our novel proteogenomics approach is focused around a customized enhanced liquid chromatography mass spectrometry (LC-MS) analysis of micro-scale and/or nano-scale tissue sections. This is achieved with a silver-stained one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (1D-SDS-PAGE) approach developed for LC-MS analysis of fresh-frozen tissue specimens obtained via LCM. This includes an in-gel digestion method adjusted and specifically designed to maximize the proteome coverage from amount-limited LCM samples to better facilitate in-depth molecular profiling. Conclusions: A proteogenomic approach is reported that is utilizing amount limited tissue quantities from microdissected fresh frozen tissue. The methodology may also be applicable to other types of specimens having limited nucleic acids, protein quantity, and/or sample volume.
Real-world monitoring and treatment patterns in von Hippel-Lindau (VHL) disease-associated central nervous system hemangioblastomas (CNS-Hb).
Authors: Eric Jonasch, Yan Song, Jonathan Freimark, Manasi Mohan, James Signorovitch, Murali Sundaram
Journal: Journal of Clinical Oncology (2024)

2086 Background: VHL disease is an inherited tumor syndrome that causes multiple benign and malignant tumors to develop; CNS-Hb is often the first VHL disease manifestation, occurring in 70-80% of patients with VHL. Patients often need many tumor treatments to manage the disease. This study evaluated disease monitoring and treatment patterns among patients with VHL-CNS-Hb. Methods: Using an algorithm based on VHL manifestations, patients with VHL were identified from Optum’s de-identified Clinformatics Data Mart Database. Patients with a CNS-Hb diagnosis were then selected. Treatment patterns were assessed among patients with VHL after their initial diagnosis of CNS-Hb. Incidence rates (IR) of the following treatments for managing CNS-Hb or other VHL-associated tumors were assessed: surgery for removal of VHL-associated tumors, renal ablation, radiotherapy, targeted therapy for RCC, and retinal laser therapy. Rates for tumor treatments were reported as events per 10-person years. Generalized linear models estimated IRs of analgesic use, VHL disease monitoring procedures, and visits to VHL-related medical specialists in the patient and control cohorts, adjusting for age, sex, the number of outpatient visits at baseline, and health plan type. Results: 220 patients with VHL-CNS-Hb were identified. Reflecting the multifaceted nature of VHL disease, the tumor treatments with the highest unadjusted IRs during the study period among these patients were targeted RCC therapies (2.15 per 10-person years), surgical removal of cerebellar and spinal hemangioblastomas (0.52 per 10-person years), and radiotherapy (0.42 per 10-person years). The tablecontains estimated adjusted IRs and IRRs for the use of select analgesics, monitoring procedures, and medical specialist visits for the VHL-CNS-Hb and comparator cohorts. Conclusions: VHL-CNS-Hb presents a multifaceted burden, involving treatments for various VHL-related tumors. Patients with VHL-CNS-Hb use more analgesics, undergo frequent monitoring, and have increased specialist visits compared with the control group. Successful tumor control holds the potential to reduce morbidity and long-term medical management associated with the disease. [Table: see text]