Citations

Abstract Background: Despite the success treating hematologic malignancies, chimeric antigen receptor T-cell (CAR T) therapies face challenges in breast cancer and other solid tumors due to lack of targets that distinguish tumor from normal cells. Epithelial growth factor receptor (EGFR) plays a critical role in oncogenesis across several cancers and is often upregulated [1]. While monoclonal antibodies targeting EGFR have demonstrated efficacy, these approaches are often limited by on-target, off-tumor toxicities, such as skin and gastrointestinal toxicity, which constrains dose escalation and efficacy [2]. A2B395 is an allogeneic, logic-gated, EGFR-targeted, TmodTM CAR T therapy designed to address these limitations and provide a convenient and consistent off-the-shelf option. This therapy incorporates 2 CARs: an activator targeting EGFR and a blocker targeting human leukocyte antigen (HLA)-A*02. The activator recognizes EGFR on both tumor and normal cells, whereas the blocker inhibits CAR T activity against normal cells (with preserved HLA expression) while allowing activation against tumor cells (with HLA-A*02 loss of heterozygosity [LOH]). This approach is designed to avoid on-target, off-tumor toxicity, a significant limitation to CAR T treatment of solid tumors [3]. To address potential graft-vs-host response, a short-hairpin RNA expression module targeting beta-2 microglobulin is included in the Tmod construct, which significantly reduces major histocompatibility complex class I levels and subsequent host immune response [4]. Importantly, the Tmod system is modular and adaptable to multiple targets. Initial data on autologous Tmod CAR T therapy suggest reduced off-tumor toxicity and encouraging clinical efficacy [5]. A2B395 represents a novel approach for targeting EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity. Methods: DENALI-1 is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B395 in adults. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA loss of heterozygosity at any time in the course of their disease via next-generation sequencing. Key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers associated with EGFR expression, including triple-negative breast, colorectal, non-small cell lung, squamous cell head and neck, and renal cell cancers. Patients must have received ≥1 line of prior therapy, such as a checkpoint inhibitor, molecular targeted therapy, or chemotherapy. The primary objective of the phase 1 portion is to evaluate safety, tolerability, and the recommended phase 2 dose (RP2D) using a Bayesian optimal interval design for dose escalation. The dose-expansion phase will confirm the RP2D and collect and analyze biomarker data. The Phase 2 portion will assess overall response rate per RECIST v1.1. As of 03 July 2025, the first patient dosed with A2B395, who has breast cancer, completed the 28-day safety review period. Dose-escalation is ongoing. Citation Format: J. M. Specht, S. R. Punekar, M. Ulrickson, D. J. Wong, J. R. Hecht, M. Maus, P. M. Grierson, J. B. Sunwoo, J. R. Molina, D. G. Maloney, K. Spencer, H. E. Fuentes Bayne, M. Davila, S. P. Patel, B. Creelan, D. B. Zhen, J. Niu, D. C. Prasad, R. L. Marar, N. A. Bagegni, G. Palluconi, J. Lee, A. Mardiros, W. Bretzlaff, W. J. Langeberg, J. S. Welch, E. Ng, W. Y. Go, K. Kirtane, R. A. Shatsky. Denali-1: a seamless phase 1/2 study of A2B395, a logic-gated, allogeneic, Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with triple-negative breast cancer and other EGFR-expressing solid tumors with HLA-A*02 loss of heterozygosity (LOH) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-03.

Abstract IBC Clear: A decentralized multi-center MRD Registry for Inflammatory Breast CancerInflammatory breast cancer is an aggressive subtype of breast cancer with distinct clinical phenotypes, including early recurrence post-tri-modal care (neoadjuvant systemic therapy, surgery, adjuvant radiation). Preliminary data from MDACC have shown a high rate of baseline and serial MRD positivity in IBC patients (35-40% at 6-12 months post-surgery), suggesting that newly diagnosed IBC is an ideal population to test MRD as a standard of care and design adjuvant interventional trials. However, to date, our understanding of the optimal monitoring cadence and interventions following MRD positivity remains limited. IBC Clear is a decentralized protocol developed to collect real-world data from patients treated amongst our IBC Connect network of 19 US-based and three international institutions (7 of whom have expressed interest in participating). Patients who have had, or plan to have Signatera® ordered at the post-chemo/pre-surgery timepoint can self-enroll from the community by emailing IBCClear@mdanderson.org for information on the consent process. Study Design: Eligibility criteria include English-speaking patients > 18 years of age with a clinical diagnosis of IBC, with Signatera testing ordered or planned. The post-chemo/pre-surgery timepoint is the only study-mandated timepoint; however, any additional serial testing conducted before or after this timepoint will also be collected. Patients who have at least one Signatera test ordered and plan to have a pre-surgery/post-chemo collection as standard of care will be enrolled in a central REDCap database. Physicians enrolling patients may act on the results according to their clinical judgment, including imaging assessments and treatment changes. These interventions will be captured in the database. An electronic EORTC QLQ C30 survey will also be administered prior to and after receiving Signatera results to gather information about the impact of testing on the patient's quality of life. A total of 200 patients from all sites will be enrolled over a period of two years. Patients will be followed remotely for up to 2 years from the first Signatera test or until clinical recurrence, whichever comes first. Endpoints: Data collected will include the feasibility of decentralized data collection studies, as well as Signatera and recurrence information. The goals are to gather real-world data regarding the association of MRD positivity with pathologic response in IBC, patient-reported QOL for worry about recurrence, median lead time between the first MRD-positive result and clinical recurrence, and, if possible, whether the adjuvant therapies decrease the amount of MRD in IBC patients (pending optional longitudinal testing). Status of the study: The study was activated in June 2025. As of abstract submission, 2 patients have been enrolled at the lead site. Collaborating sites are being added. Sponsor: The University of Texas MD Anderson Cancer Center Clinicaltrials.gov Accession number: NCT06966050 Citation Format: A. Alexander, M. Kai, K. A. Abou-Hussein, S. Ali, C. Anderson, S. W. Bahadur, Y. C. Cheng, N. T. Ueno, X. Wang, A. Lucci, W. A. Woodward, S. Saleem, MDACC Inflammatory Breast Cancer Team. PS2-02-05: Ibc clear: a decentralized multi-center mrd registry for inflammatory breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-02-05.

INTRODUCTION: Chronic gastroduodenal disorders are highly prevalent and encompass heterogeneous pathophysiology. Autonomic dysfunction may contribute, but its relative contribution to disease pathophysiology and symptoms is unclear. This study aimed to clarify the contributions of autonomic dysfunction in gastroduodenal disorders and symptom associations using multimodal testing, hypothesizing that distinct disorder subgroups would be revealed. METHODS: This prospective observational cohort study included 80 patients with chronic gastroduodenal symptoms. Participants underwent expert clinician-led autonomic evaluation, body surface gastric mapping (BSGM; Gastric Alimetry, New Zealand), and gastric emptying scintigraphy testing. BSGM phenotyping, gastric emptying cutoffs, and autonomic criteria followed standard criteria. RESULTS: Gastroparesis was diagnosed in 27 (33.8%) patients. Autonomic dysfunction was present in 21 (26.3%) patients, and abnormal BSGM in 20 (25%). Autonomic dysfunction and abnormal BSGM were both more prevalent in gastroparesis (51.9% vs 13.2%, P = 0.001; and 44.4% vs 15.1%, P = 0.005, respectively). However, these diagnoses tended not to overlap, with patients having autonomic dysfunction generally exhibiting normal BSGM tests. Autonomic dysfunction independently predicted delayed gastric emptying (OR 13.8, P < 0.001) and was associated with earlier meal responses (higher meal response ratio, P = 0.04) and worse postprandial distress symptoms ( P < 0.05). DISCUSSION: Autonomic dysfunction independently predicted delayed gastric emptying and revealed a gastroparesis mechanism distinct from gastric myoelectrical impairment. Autonomic dysfunction altered the postprandial gastric motor response and was associated with a greater symptom burden. Multimodal physiological testing including autonomic profiling reveals distinct mechanistic subgroups in patients with chronic gastroduodenal symptoms.

ABSTRACT Background One in five emergency department (ED) visits is by older adults aged 65+ years. Clinical practice guidelines are needed to optimize patient care by translating the best available evidence into actionable recommendations to guide person‐centered management for this medically complex and growing patient population. Our objective was to understand contributors' experiences and share best practices to inform other guideline working groups. Methods We conducted a qualitative study based on thematic analysis with an interpretivist paradigm in June–July 2025, using semi‐structured interviews of Geriatric Emergency Department (GED) Guidelines 2.0 contributors to understand their experiences. Interviews were transcribed, independently reviewed by team members, and reflexively coded to identify themes. Results We interviewed 18 participants. Four main themes emerged: (1) motivations for participation, (2) varying opportunities to be involved, (3) personal benefits, and (4) challenges for improvement. Participants contrasted the strengths of shared learning and development with the burdens of organization and coordination. Conclusion Contributors to the GED Guidelines 2.0 reported a positive experience. They joined because they wanted to contribute to better care of older patients and to achieve personal and professional goals. Many cited that their roles aligned with their strengths and expertise. They also gained skills and knowledge on systematic reviews and benefited from networking. Future groups planning a similar process should consider having multiple levels of leadership, experts in systematic reviews, regular reminders, and creative incentives to improve the process and foster improved networking opportunities within their disciplines.

Abstract In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

Abstract High-grade gliomas (HGGs) are aggressive tumors with poor outcomes and limited treatment options. Here, we combined genomic and transcriptomic tumor profiling with drug testing in a patient-derived 3-dimensional culture model to identify individualized treatments and predictive biomarkers. Activity of single agents targeting frequently dysregulated glioma pathways was relatively poor ex vivo and generally reflected historical patient data. However, compounds targeting PI3K, epigenetic, and survival/senescence signaling were effective in some cases. Drug sensitivity correlated with transcriptional rather than genomic features and suggested heterogeneity as a resistance mechanism. Bromodomain and extraterminal domain inhibition was particularly effective in tumors enriched in the mesenchymal transcriptional subtype, promoted proneural transition, and was overcome by upregulated PI3K signaling. Notably, combinations were largely effective, with 6 strategies exhibiting stronger efficacy than corresponding single agents in most cases (58-77%). This study identifies HGG vulnerabilities and associated biomarkers, resistance mechanisms, and effective combination strategies that warrant further clinical validation. Graphical Abstract

ABSTRACT Intraocular lymphomas, including vitreoretinal and choroidal lymphoma, can simulate the clinical presentation of other benign and malignant ocular diseases resulting in diagnostic delays. Multimodal imaging features can raise early clinical suspicion to support appropriate subspecialty referrals and treatment for patients affected by these conditions. This review synthesises current evidence on the diagnostic and prognostic value of characteristic imaging features of these rare malignancies. Findings are reviewed based on imaging modality, including fundus photography, optical coherence tomography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, optical coherence tomography angiography, and ultrasound. We emphasise discriminative biomarkers that heighten suspicion for either vitreoretinal or choroidal lymphoma, as well as key findings to discriminate between lymphoma and alternative diagnoses. We further describe longitudinal changes in multimodal imaging features that can facilitate tracking disease progression or treatment response. By consolidating modality‐specific findings, this review aims to facilitate early referral and accurate diagnosis of these rare malignancies.

Abstract INTRODUCTION Tau species lacking truncation of the N‐terminal region, including plasma N‐terminal tau fragment 1 (NT1), have been previously associated with cognitive decline, neurodegeneration, and tau pathology in late‐onset sporadic Alzheimer's disease (AD). METHODS Here, we examined cross‐sectional and longitudinal plasma NT1 as a possible predictor of cognitive, clinical, and core AD biomarker trajectories in autosomal dominant AD (ADAD). RESULTS NT1 levels in ADAD mutation carriers (MC; n = 132) increased across the disease continuum, compared to non‐carriers (NC; n = 75), becoming elevated about a decade prior to estimated symptom onset. Cross‐sectional and longitudinal NT1 levels in MC were associated with clinical, cognitive, and biomarker changes. NT1 increases continued in symptomatic phases of disease, a distinct trajectory from that seen with CSF p‐tau217 and other phospho‐tau species. DISCUSSION Together, our results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related clinical, cognitive, and biomarker outcomes. Highlights Leveraging a deeply phenotyped cohort of individuals carrying a pathogenic variant for autosomal dominant Alzheimer's disease (ADAD) and their non‐carrier family members, our results suggest that plasma N‐terminal tau fragment 1 (NT1) levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with cerebrospinal fluid (CSF) measures of tau pathology but less so with CSF or imaging measures of β‐amyloid pathology. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1—alone or combined with other tau measures—may be useful in studying AD‐related tau pathology and neurodegeneration across a wide spectrum of disease.