Citations

Abstract Transcription factors and their cofactors are major and selective nononcogene dependencies in multiple myeloma cells. By performing a gain-of-function perturbation screen in human multiple myeloma cell lines, we identified the inhibitor of DNA binding (ID) genes as putative suppressors of multiple myeloma cell fitness. Among them, ID2 was found to be downregulated in multiple myeloma patient cells and acted as a tumor suppressor by directly binding and repressing the basic helix-loop-helix factor TCF3, also known as E2A. Lower ID2 expression in multiple myeloma cells conferred a proliferative advantage by increasing TCF3 activity, leading to a dependency on this transcription factor. In contrast, ID2 overexpression reduced TCF3 binding to DNA, which resulted in cell-cycle arrest and a halt in multiple myeloma cell proliferation. The myeloma bone marrow milieu supported this process by further decreasing the expression of ID2 and enhancing TCF3 activity, partly via IL6, revealing a mechanism by which the tumor microenvironment affects multiple myeloma cell behavior. Significance: Multiple myeloma cells exploit the oncogenic and proliferative potential of TCF3 by downregulating the transcriptional regulator ID2, a process facilitated by the bone marrow microenvironment.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Abstract Background High-grade gliomas (HGG) have a poor prognosis despite aggressive treatment. Severe, persistent lymphopenia occurring in HGG patients after concurrent chemoradiation is associated with worse survival. NT-I7, a long-acting interleukin-7 analog, has been shown to increase CD4 and CD8 counts in healthy, septic, and HIV-positive adults. This multi-institutional, NCI-funded dose-escalation trial is the first to evaluate NT-I7 safety and activity in HGG patients with severe treatment-related lymphopenia (TRL) and the effect of co-administered glucocorticoids. Methods Eligible HGG patients had CD4 counts <300 cells/mm3 after 5 weeks of standard chemoradiation and were receiving either ≤0.75 or ≥4 mg/day of dexamethasone. Patients received a single intramuscular dose of NT-I7 (60 or 360 µg/kg) post-chemoradiation, followed by safety evaluation and multi-parameter, longitudinal monitoring of lymphocyte populations and immunologic function. Results NT-I7 was well tolerated in all 12 patients (median age 64; median CD4 count 161 cells/mm³) before the study closed prematurely. Absolute lymphocyte counts doubled in 83% (10/12; 95% CI: 51.6%-97.9%) of patients, and CD4 counts doubled in 42% (5/12; 95% CI: 15.2%-72.3%) of patients. Glucocorticoid use did not significantly affect CD4 or lymphocyte increases. Correlative immune profiling revealed increased Ki67 expression in CD4 (P < .005) and CD8 (P < .05) after one week, along with the expansion of CD4 and CD8 T-cell subsets and CD56 + natural killer cells. Conclusions NT-I7 is well tolerated and effectively increases lymphocyte and CD4 counts in severe TRL patients, regardless of glucocorticoid use, suggesting its potential to mitigate TRL and improve outcomes in HGG.

Background: High-grade gliomas (HGGs), particularly glioblastoma (GBM), are associated with exceptionally high mortality and inevitable recurrence. In considering novel treatment options for these devastating diseases, immunotherapies represent promising candidates. Immunotherapies have demonstrated efficacy for several advanced tumors outside the central nervous system, highlighting a potential role for these agents in treating HGGs. However, multiple challenges to immunotherapy efficacy have tempered therapeutic benefit in practice, including local and systemic immunosuppression, intratumoral heterogeneity, and various mechanisms of intrinsic and acquired resistance. In the past 30 years, diverse immunotherapeutic subclasses have been assessed for benefit against HGGs. Methods: We performed a PubMed search for randomized clinical trials performed within the last 30 years evaluating the following immunotherapy agents for high-grade gliomas: immune checkpoint inhibitors, vaccines, oncologic viruses, cytokines, and CAR T-cells. The present review offers a critical analysis of key pre-clinical and clinical trials that have shaped the immunotherapy landscape for high-grade gliomas over the past two decades. Results/Conclusions: Across the different immunotherapeutic methods and modalities explored thus far, a recurring theme emerges: while therapeutic strategies with a compelling conceptual basis are continually under development and even demonstrate a benefit in preclinical and early-phase trials, larger and later-phase trials consistently fail to produce concordantly significant outcomes. To date, no large-scale clinical trial has demonstrated a benefit of sufficient consequence to change practice. Continued critical appraisal of the strengths and pitfalls of prior investigative work, optimization of treatment development and delivery, and innovative approaches to combination therapy design will collectively be integral to future therapeutic advancement.

e13893 Background: For individuals with CNS tumors who have experience difficulties with in-person (IP) evaluations due to disease-related neurologic disability or the costs associated with travel, telehealth (TH) offers a convenient and timely alternative for accessing specialized neuro-oncology care. We report our institution’s experience with telehealth utilization in neuro-oncology. Methods: We conducted a retrospective review of patients who had at least one neuro-oncology telehealth visit between August 2021 and May 2024 at Mayo Clinic in Rochester, Minnesota. Reasons for visits, outcomes of appointments, acute care utilization following visits was reviewed. Results: A total of 660 patients who had at least one TH visit between August 2021 and May 2024 were included in the analysis. Median age was 56 (range 20-98), 49% were female, and 92% were white. Most patients resided in the US Midwest (84%), followed by the South (8%), West (5%), Northeast (1%), and US Territories (< 1%). Less than two percent were international patients. The most common primary visit diagnosis was glioblastoma (GBM, 26%), followed by astrocytoma, IDH-mutant (17%), meningioma (17%), oligodendroglioma, IDH-mutant, 1p/19q codeleted (7%). Of 6657 visits reviewed, 2745 (41%) were conducted via TH. Telehealth visits served various purposes, including consultation for newly diagnosed tumors or abnormal MRIs (n = 26), second opinion for an established tumor diagnosis (n = 119), discussion about clinical trial participation (n = 108), tumor-related treatment discussions (n = 719), chemotherapy education (n = 161), new symptom assessment (n = 117), symptom management (n = 366), and tumor surveillance (n = 1694). Outcomes from telehealth visits included enrollment in clinical trials (n = 28), proceeding with tumor-directed surgery (n = 46), initiation of radiation therapy (n = 88), starting or changing systemic therapy (n = 377), continuing existing systemic therapy (n = 932), transition to supportive care (n = 45), tumor diagnostic workup (n = 28), continuation of tumor surveillance (n = 1254). Acute care utilization, defined as an emergency department visit or hospitalization within one month of an appointment, was the same following telehealth visits compared to in-person visits (6.9% for IP vs 5% for TH, p = 0.507). Conclusions: Our findings demonstrate that telehealth can effectively support all aspects of neuro-oncology care, ranging from initial diagnosis discussions to systemic therapy management and transitions to supportive care. Telehealth offers a convenient and accessible method of care delivery option for patients faced with neurologic illness. Additionally, THs do not lead to increased acute care utilization compared to IP evaluations.

e13891 Background: Most patients with central nervous system (CNS) malignancy develop cognitive impairment, fatigue, and mood-related symptoms that are impacted by cancer and treatment, including radiation therapy. We currently have limited therapies to mitigate neurocognitive toxicity. It is important to accurately assess neurocognitive function and symptom burden when working to establish therapeutics. The objective of this trial is to assess the effectiveness of therapies aimed at improving neurocognitive function and quality of life by leveraging a decentralized approach incorporating an established digital neurocognitive assessment tool and development of a remote symptom collection/medication log to improve capture of longitudinal neurocognitive data. Methods: This is an open-label decentralized clinical trial (NCT06377696) that randomizes patients who have received intracranial radiation for primary and secondary brain tumors in a 1:1 allocation to health promotion with a wearable device +/- metformin (targeting radiation-related toxicity). Remote symptom collection is reported through digital patient surveys. Medication adherence is being monitored through a digital medication log developed for the study. Remote neurologic examination is performed by clinical neuro-oncologists at telehealth visits. Participants perform serial remote cognitive assessments with an established digital neurocognitive testing platform – Mayo Test Drive (MTD). Cognitive assessments and symptom surveys were designed to be completed on a smartphone, tablet, or computer device. Results: The study started enrollment on May 31, 2024. As of January 27, 2025, 54 of 100 planned participants have enrolled (27 on each arm). 51 participants remain active on trial; 3 withdrew from trial participation (2 prior to treatment, 1 after treatment). The overall completion rate for a quality-of-life questionnaire (EORTC QLQ-C30) is 85.0%, and each dose of metformin logged is 78.5%. The overall completion rate for virtual neurologic examination and short test of mental status is 94.7%. For MTD, the overall completion rate is 97.9%. The average MTD session duration was 16 minutes. Most participants completed MTD testing using a smartphone (90.5%) at home (89.1%). Conclusions: These results provide preliminary support that a decentralized trial assessing neurocognitive outcomes is feasible in patients with CNS malignancy. The completion rates of questionnaires and objective cognitive evaluation are comparable or higher than expected with historic norms. Final study results will provide real-world cognitive and quality-of-life data for patients with CNS tumors while providing preliminary data on the effectiveness of device-based health promotion +/- metformin for treatment related cognitive decline. Clinical trial information: NCT06377696 .

2053 Background: Recurrent gliomas are highly aggressive brain tumors, often resistant to conventional treatments. Immune checkpoint inhibitors (ICI) have emerged as promising therapeutic agents by targeting tumor cells through immune modulation. However, clinical trials have demonstrated limited efficacy in recurrent gliomas. This study aimed to identify potential factors influencing treatment efficacy of ICIs in recurrent gliomas. Methods: This retrospective study, conducted across the Mayo Clinic following IRB approval, included patients ≥ 18 years diagnosed with adult-type diffuse gliomas. Eligible patients received treatment with at least 2 cycles of ICI for recurrent glioma between 2014 – 2024. Patients treated with ICIs as initial therapy were excluded. Clinical, radiographic, histological, and molecular data were analyzed, with missing information excluded. Responders to ICI were defined as patients who did not meet iRANO criteria for progressive disease based on first radiographic response assessment (and confirmatory follow up imaging as needed for possible pseudo-progression). Survival outcomes [Progression-Free Survival (PFS) and Overall Survival (OS)] and potential predictive variables were analyzed using the Kaplan-Meier method and Cox-Regression Analyses. Results: 67 patients met eligibility criteria (mean age: 45.1 ± 15.0 years; 64.2% male; 94% white). 64 (95.5%) patients received Pembrolizumab, 2 (3%) Nivolumab, and 1(1.5%) combined Ipilimumab/Nivolumab, with a median treatment duration of 2.77 (1.39 – 19.4) months. All had prior alkylating chemotherapy. The OS (from diagnosis) for IDH wildtype (IDH-WT, n = 36), IDH mutant, 1p/19q non-co-deleted (IDH-MUT, n = 17) and IDH mutant, 1p/19q co-deleted (OLIGO, n = 14) gliomas were 3.1, 9.2, and 18.6 years, respectively. The median PFS from time of ICI was 2.23 (0.69 – 27.3) months. 24 (36.9%) patients were identified as Responders. PFS was not significantly different between patients with IDH-MUT and IDH-WT gliomas (2.30 vs 2.07 months, p = 0.593). However, patients with OLIGO gliomas had a significantly higher PFS compared to IDH-WT gliomas (5.16 vs 2.07 months, p = 0.021). The proportion of responders was greatest in OLIGO gliomas, however, did not reach statistical significance (IDH-WT, 31.4%; IDH-MUT, 29.4%; OLIGO, 61.5%, p = 0.120). Overall PFS was not impacted by patient age, sex, and extent of initial resection. When analyses were limited to Responders, the PFS for IDH-WT, IDH-MUT and OLIGO gliomas were 5.75, 7.01 and 10.8 months, respectively ( p = 0.434). Conclusions: Patients with recurrent OLIGO gliomas may have a longer PFS with ICI therapy compared with recurrent IDH-WT and IDH-MUT gliomas. However, there is significant variability in ICI treatment efficacy between patients. Further molecular profiling is in progress to evaluate additional predictive biomarkers of response.

TPS2099 Background: Gliomas are the most common primary central nervous system (CNS) malignancy in adults, accounting for 26.3% of all brain tumors. Care at high volume centers is associated with an overall survival benefit, but access to in-person evaluations can be challenging due to disease-related neurological disability and loss of income. Telehealth represents a convenient and efficient alternative to in-person evaluations, but acceptability and comparative safety of this care delivery modality has not been prospectively evaluated among glioma patients undergoing chemotherapy. Methods: This single-arm non-randomized pragmatic clinical trial evaluates patient satisfaction with, and safety of video-enabled telehealth assessments compared to in-person evaluations for patients with glioma undergoing temozolomide chemotherapy. The study includes adult patients with a diagnosis of glioma requiring adjuvant temozolomide chemotherapy. Participants act as their own controls, alternating between in-person and telehealth assessments while undergoing chemotherapy dosed per standard of care. Monitoring labs are completed locally and transmitted electronically. For participants without access to Wi-Fi or a device (e.g. mobile phone or computer), cellular-enabled tablet devices are provided to facilitate appointments and completion of electronic study components. All participants who travel to in-person appointments are reimbursed for travel expenses. The primary outcome measure is patient satisfaction with care delivered, as measured by institutional Press-Ganey survey scores obtained following telehealth and in-person assessments. A key secondary outcome measure is completion rate of planned oral chemotherapy, tracked using a digital pill diary incorporated into our institutional electronic health record. The digital diary allows real-time tracking of chemotherapy adherence and adverse events experienced by participants. Other secondary outcomes include acute care utilization days following telehealth and in-person visits (defined as emergency department evaluations and days of inpatient stay), neurologic disability as measured by the Neurologic Assessment in Neuro-Oncology (NANO) scale, and disease related quality of life measured by the EORTC QLQ-C30. All participant surveys are self-reported and completed electronically. This decentralized pragmatic clinical trial provides unprecedented, prospective real-world data on utilization of telehealth services compared to in-person visits for patients undergoing chemotherapy for glioma. We expect the data generated to inform the design and conduct of future decentralized interventional neuro-oncology trials. NCT06625047 opened for enrollment in October 2024, 16 of 30 intended participants were accrued as of January 2025. Clinical trial information: NCT06625047 .