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Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 for oncogenic activation in GBM, yet targeting EGFRvIII has yielded limited clinical success to date. In this study, we employed patient-derived xenograft (PDX) models expressing EGFRvIII to determine the key points of therapeutic vulnerability within the EGFRvIII-STAT5 signaling axis in GBM. Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). STAT5 phosphorylation is independent of JAK1 and JAK2 signaling, instead requiring Src family kinase (SFK) activity. Saracatinib, an SFK inhibitor, attenuates phosphorylation of STAT5 and preferentially sensitizes EGFRvIII+ GBM cells to undergo apoptotic cell death relative to wild-type EGFR. Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival.

e14535 Background: Cytokine release syndrome (CRS) is the most common complication of chimeric antigen receptor T cells (CAR-T) for hematologic malignancies. We hypothesized that patients undergoing CAR-T therapy who are on metformin will experience a lower incidence or severity of CRS than patients not on this medication. Methods: We evaluated all patients treated with CAR-T at Mayo Clinic Rochester between 1/1/2018 and 1/31/2023, and abstracted relevant clinical and laboratory characteristics to determine the incidence and severity of CRS, PFS as well as OS in patients who were, or were not, on metformin before and during CAR-T therapy for Type 2 diabetes mellitus. We used the Chi-Square test, Mann-Whitney test and the Kaplan-Meier method to analyze data. Results: In the 5-year interval under consideration 237 patients received CAR-T, 168 for non-Hodgkin lymphoma (NHL), and 69 for multiple myeloma (MM). 23 patients (15 NHL and 8 MM) were on metformin at the time of CAR-T. 15 patient developed CRS while on metformin and 175 patients not on metformin (p=0.05). Grade 3 or 4 CRS incidence was 4% in both groups (p=0.41). Of the 153 patients with NHL not on metformin, 121 developed any grade of CRS, while 10 of 15 patients on metformin developed CRS (p=0.268). 4 NHL patients developed CRS Grade ≥3 or higher, while 0 of 15 on metformin developed Grade ≥3 CRS (p=0.237). For the MM patients, the incidence of CRS was 49 patients not on metformin and 5 patients on metformin (p<0.001). 3 MM patients developed CRS Grade ≥3 or higher, while 0 of 8 on metformin developed Grade ≥3 CRS (p=0.346). 12 of 15 patients on metformin with NHL achieved CR compared to 92 of 153 patients not on metformin (p=0.1305). 3 of 8 patients with MM on metformin compared to 24 of 61 patients with MM not on metformin achieved CR or better post CAR-T (p=0.92). Tocilizumab was used in 40% of patients on metformin but in 66% of patients not on metformin (p=0.0016). In NHL patients, PFS from CAR-T infusion was not reached (range: 6.3 to NR) for patients on metformin versus 9.9 months (range: 6.3–19.5) in patients not on metformin (p = 0.3332). In the MM patients, progression-free survival (PFS) from CAR-T infusion was 8.4 months (95% CI: 7.9–not reached [NR]) for patients on metformin and 22.6 months (13.7–NR) for those not on metformin (p = 0.07). Median OS for NHL patients on metformin was not reached (9.766–NR) versus 32.6 months (18.6–NR) for patients not on metformin (p = 0.7022). Median OS was 17 months (95% CI: 8.3 to NR) for patients with MM on metformin vs NR (95% CI: 9.4 to NR) for patients not on metformin (p = 0.2559). Conclusions: In this retrospective study, the co-administration of metformin during CAR-T cell therapy for NHL and MM appears to be associated with a numerically reduced incidence of CRS. The effect appears to be particularly marked in patients with multiple myeloma. Metformin therapy did not seem to affect the response to CAR-T therapy in either NHL or MM.

1559 Background: Timely access to specialty Palliative Care (SPC) services provides significant benefits to hospitalized patients with cancer, including improvements in quality of life. However, many patients with cancer who could benefit from SPC suffer from lack of timely referral or do not receive SPC services. A previously published trial of an artificial intelligence/machine learning (AI/ML) model to predict need for SPC at Mayo Clinic increased timely SPC consultation of hospitalized patients overall. We sought to review the performance of this algorithm in patients with cancer across an expanded hospitalized population. Methods: The study population consisted of all patients admitted into a Mayo Clinic hospital in Minnesota, Wisconsin, Arizona and Florida between January 2020 and September 2023. Due to the size of the cohort a case-control sample of three controls for every case was created. Patients were considered to be a patient with cancer if they had at least one billing diagnosis up to 1 year prior to their index hospitalization from any of the 5 HCC categories denoting cancer: Metastatic Cancer and Acute Leukemia (HCC 8); Lung and Other Severe Cancers (HCC 9); Lymphoma and Other Cancers (HCC 10); Colorectal, Bladder, and Other Cancers (HCC 11); and Breast, Prostate, and Other Cancers and Tumors (HCC 12). The training data set consisted of 107,076 patient encounters with a total of 8,355,090 time periods of constant risk. An AI/ML model using gradient boosting methods which contained 269 variables (both static and time-varying) of various classes with SPC consultation treated as a time-to-event outcome was trained. Results: Due to the longitudinal nature of the prediction, performance was assessed using the max score AUC (using the max score a patient received during a given encounter prior to an event or discharge) to produce the AUC. The model had an overall AUC of 0.932 (0.929, 0.935 – 95% CI). We saw a decrease in performance of the AI/ML model in the Oncology population with an overall performance of 0.818 (0.806, 0.83). Some of the most influential variables were previous SPC visit, age, metastatic disease, acute leukemia diagnosis, and pain scores. Conclusions: An AI/ML model can effectively predict the need for an inpatient PC consult in a population of hospitalized patients with cancer. [Table: see text]

Abstract Chimeric antigen receptor T‐cell (CAR‐T) therapy, despite being a potentially curative therapy in relapsed or refractory (RR) large B‐cell lymphoma (LBCL), remains underutilized in older patients due to limited clinical data. We therefore studied the safety and efficacy of CAR‐T therapy in older patients with RR LBCL in the real‐world setting. Patients aged ≥65 years with RR LBCL, treated with anti‐CD19 CAR‐T therapy at 7 US institutions were included in this multicenter, retrospective, observational study. In total, 226 patients were included. Median age at infusion was 71 years (range 65–89). Best objective and complete response rates were 86% and 62%, respectively. Median follow‐up after infusion was 18.3 months. The median progression‐free survival (PFS) was 6.9 months, with 6‐ and 12‐month PFS estimates of 54% and 44%, respectively. The nonrelapse mortality (NRM) rate was 10.9% at day 180, primarily due to infections, and not impacted by the age groups. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 7% and 26%, respectively. In univariate analysis, no significant difference in PFS was seen regardless of the age groups or CAR‐T type, whereas ECOG PS ≥2, elevated LDH, bulky disease, advanced stage, extranodal involvement, the need for bridging therapy, and prior bendamustine exposure were associated with shorter PFS. These findings support the use of CAR‐T in older patients, including those aged ≥80 years. The age at CAR‐T therapy did not influence safety, survival, and NRM outcomes. Older patients should not be excluded from receiving CAR‐T therapy solely based on their chronological age.

11176 Background: Progression-free survival (PFS) is frequently measured in oncology clinical trials. In analyses outside of the trial setting, various strategies have been utilized to assess real-world PFS (rwPFS), including manual abstraction of clinical records, natural language processing (NLP) of oncology notes and radiology reports, and longitudinal analyses of radiologic images. Here we develop and validate a new semi-automated workflow that combines NLP of clinical notes with structured electronic health record data to facilitate the evaluation of rwPFS in patients with metastatic breast cancer (mBC). Methods: This study analyzes de-identified EHR data using nference nSights. The data is extracted following privacy-preserving protocols and is HIPAA compliant. The overall cohort included 316 patients with HR-positive, HER2-negative mBC who initiated Palbociclib and Letrozole combination therapy between January 1, 2015 and December 31, 2021. We developed and implemented an ensemble of deep-learning NLP frameworks to capture progression events from unstructured clinical notes and radiology reports. A change in the line of therapy, as determined by structured drug order/administration records, was also considered a progression event. We used manually curated “ground-truth” datasets to evaluate the performance of the progression-event capture workflow at the levels of both sentences (N = 1000) and patients (N = 100) by calculating sensitivity, specificity, precision, accuracy, and F1 scores. Progression events and censoring events (death, loss to follow-up, end of study period) were considered to compute rwPFS. Results: At the sentence level, progression events were captured from clinical notes and radiology reports with a sensitivity of 99.8%, specificity of 96.7%, and accuracy of 98.2% (Table). At the patient level, initial progression was correctly captured within a window of +/-30 days with a sensitivity of 92.5%, specificity of 83.0%, and accuracy of 88.0% (Table). In a sample of 100 patients, the median rwPFS was determined to be 25 months (95% CI; 15-35 months) by manual curation and 22 months (95% CI; 15-35 months) by the semi-automated workflow. In the overall cohort, median rwPFS was 20 months (95% CI; 18-25 months). Conclusions: An ensemble of NLP algorithms extracted progression events from clinical notes and radiology reports with high accuracy. A semi-automated workflow enabled rapid and accurate determination of rwPFS in mBC patients receiving a combination chemotherapy regimen. Further evaluation of this workflow to estimate rwPFS in other cancers and therapeutic settings is warranted. [Table: see text]

1604 Background: Diversity in clinical studies is essential to address health disparities, but racial and ethnic minorities are often underrepresented in clinical studies, especially in precision medicine studies using genetic data (1). BASECAMP-1 (NCT04981119) is an ongoing prescreening study to identify patients with unresectable advanced or metastatic solid tumors and tumor-associated HLA-A*02 LOH for the EVEREST-1 and -2 Tmod chimeric antigen receptor T-cell therapy trials. When enrollment began in 2021, eligibility for Part 1 was restricted to patients with germline HLA-A*02:01 based on preclinical data. Additional analysis revealed the blocker in the Tmod construct had activity across HLA-A*02 subtypes (Mock, et al. Mol Ther Oncolytics.2022). Eligibility for Part 1 was then expanded to all HLA-A*02 subtypes, allowing enrollment of more diverse patient populations. HLA-A*02 allele subtypes vary by ethnicity and race; the frequency of HLA-A*02:01 is 96% in non-Hispanic Whites, but ranges from 53% to 73% in other ethnicities and races. The frequency of all other HLA-A*02 allele subtypes (HLA-A*02:XX) is <5% in non-Hispanic Whites but up to 66% in other ethnicities and races (2,3). Methods: Patients eligible for BASECAMP-1 were identified at United States study sites. All patients screened before January 16, 2024, for Part 1 were included for demographic and central lab HLA-A typing. The % increase in eligibility and % of heterozygous HLA-A*02 patients with HLA-A*02:XX were calculated by ethnicity and race. Results: A total of 1124 patients were screened for germline HLA-A*02 typing; 431 patients were HLA-A*02:01 heterozygous, of whom 37 (9%) were Hispanic, 14 (3%) African American (AA), 2 (<1%) American Indian or Alaska Native, 17 (4%) Asian or Pacific Islander (API), and 324 (75%) non-Hispanic White (Table). The eligibility expansion identified 62 patients with HLA-A*02:XX heterozygosity, of whom 6 (10%) were Hispanic, 6 (10%) AA, 19 (31%) API, and 25 (40%) non-Hispanic White. Conclusions: By expanding enrollment to include HLA-A*02:XX, 16% more Hispanic, 43% more AA, and 112% more API patients were identified, improving the diversity in this trial compared with that of initial enrollment. 1. Aldrighetti, et al. JAMA Netw Open 2021. 2. Ellis, et al. Human Immunol. 2000. 3. Gragert, et al. Human Immunol.2013. Clinical trial information: NCT04981119 . [Table: see text]

538 Background: The phase 3 PALLAS trial compared 2 years of the CDK4/6 inhibitor palbociclib with endocrine therapy of provider choice, versus endocrine therapy alone, as adjuvant treatment for patients (pts) with Stage II-III hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer. The SET2,3 index adjusts the measurement of SETER/PR index of endocrine receptor-related transcriptional activity with a baseline prognostic index (BPI) derived from tumor size (T), number of involved lymph nodes (N) and gene expression levels of ESR1, PGR, ERBB2 and AURKA (RNA4 subtype score). High SET2,3 (index ≥ 2.10) represents high endocrine sensitivity with favorable prognosis. Clinical outcome results from PALLAS were previously published, and the trial now has 5-year median follow-up. Methods: Participants in PALLAS provided a tumor tissue block prior to randomization. RNA was extracted from samples with sufficient tumor tissue and cellularity (>25mm2 with ≥20% cancer nuclei). SET2,3 index was measured from 300ng total RNA using the QuantiGene Plex platform (ThermoFisher, Waltham, MA) following the manufacturer’s protocol and using pre-defined quality control (QC) parameters and cut point. Results from primary tumor samples prior to systemic therapy were analyzed. Invasive disease-free survival (iDFS) was summarized with Kaplan-Meier plots using log-rank test. Cox models were adjusted for treatment arm assignment, with a treatment arm by SET index value interaction term to test for prediction of palbociclib benefit. The pre-defined level of significance was a two-sided 0.05. Results: There were 4075 pts from the total PALLAS population (N=5796) who provided a primary tumor sample that met pre-analytical requirements to perform the SET assay, from which 3388 (83%) results passed quality control, including 3093 from a sample obtained prior to receiving systemic therapy (1559 in palbociclib arm and 1534 in the control arm). SET2,3 index could not be calculated for 12 pts due to missing tumor or nodal information. There was no evidence of an interaction between treatment arm and SET indices (continuous) for iDFS: SET2,3 index interaction p=0.12 and SETER/PR index interaction p=0.92. Estimated 5-year iDFS was superior for those with high SET2,3: iDFS was 91.4% (95%CI 89.9–92.8) in 1719 (55.8%) pts with high SET2,3, versus 78.5% (95%CI 76.0–80.8) in 1362 (44.2%) pts with low SET2,3 (HR 0.38, 95%CI 0.31–0.47, p<0.0001). The SETER/PR index was also significantly associated with iDFS (HR 0.70 per 0.5 units, 95%CI 0.65–0.77, p<0.0001). Conclusions: There was no evidence that the SET2,3 or SETER/PR index of endocrine-related transcriptional activity predicts benefit from palbociclib treatment. SET2,3 index was strongly prognostic for pts with Stage II-III breast cancer, with excellent 5-year IDFS for pts classified as SET2,3 high. Clinical trial information: NCT02513394 .

AbstractBackgroundPrecursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma‐derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology of MM.MethodsThis study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet‐poor peripheral blood plasma of MGUS (n = 9) and MM (n = 12) patients using the size exclusion chromatography‐based method and evaluated their proteome using a label‐free proteomics workflow.ResultsIn total, 2055 proteins were identified in SEVs, while 2794 proteins were identified in LEVs. The transferrin receptor (or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher in the LEVs derived from MM patients than in MGUS patients.ConclusionsThis study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest.

Objective: Cuffless blood pressure measurement technologies have attracted significant attention for their potential to transform cardiovascular monitoring. This updated narrative review thoroughly examines the challenges, opportunities, and limitations associated with the implementation of cuffless blood pressure monitoring systems. By summarizing the current state of the art and identifying future directions, this article aims to participate in the debate around cuffless BP measurement while contributing substantial scientific value to this rapidly evolving field. Design and method: The search procedure involved using Google Scholar and PubMed databases. During the initial search, a substantial number of articles unrelated to this literature survey were retrieved. Authors then selected the articles that were relevant for this review on cuffless noninvasive BP measurement. Results: Diverse technologies, including photoplethysmography, tonometry, and ECG waveform analysis, enable cuffless blood pressure measurement and are integrated into devices like smartphones and smartwatches. Signal processing emerges as a critical aspect, dictating the accuracy and reliability of readings. Despite its potential, the integration of cuffless technologies into clinical practice faces obstacles, including the need to address concerns related to accuracy, calibration, and standardization across diverse devices and patient populations. The development of robust algorithms to mitigate artifacts and environmental disturbances is essential for extracting clear physiological signals. Based on extensive research, this review emphasizes the necessity for standardized protocols, validation studies, and regulatory frameworks to ensure the reliability and safety of cuffless blood pressure monitoring devices and their implementation in mainstream medical practice. Interdisciplinary collaborations between engineers, clinicians, and regulatory bodies are crucial to address technical, clinical, and regulatory complexities during implementation. Conclusions: While cuffless blood pressure monitoring holds immense potential to transform cardiovascular care. The resolution of existing challenges and the establishment of rigorous standards are imperative for its seamless incorporation into routine clinical practice. The emergence of these new technologies shifts the paradigm of cardiovascular health management, presenting a new possibility for non-invasive continuous and dynamic monitoring. The concept of cuffless blood pressure measurement is viable and more finely tuned devices are expected to enter the market, which could redefine our understanding of blood pressure and hypertension.

Repair and regeneration of a diseased lung using stem cells or bioengineered tissues is an exciting therapeutic approach for a variety of lung diseases and critical illnesses. Over the past decade, increasing evidence from preclinical models suggests that mesenchymal stromal cells, which are not normally resident in the lung, can be used to modulate immune responses after injury, but there have been challenges in translating these promising findings to the clinic. In parallel, there has been a surge in bioengineering studies investigating the use of artificial and acellular lung matrices as scaffolds for three-dimensional lung or airway regeneration, with some recent attempts of transplantation in large animal models. The combination of these studies with those involving stem cells, induced pluripotent stem cell derivatives, and/or cell therapies is a promising and rapidly developing research area. These studies have been further paralleled by significant increases in our understanding of the molecular and cellular events by which endogenous lung stem and/or progenitor cells arise during lung development and participate in normal and pathological remodeling after lung injury. For the 2023 Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, scientific symposia were chosen to reflect the most cutting-edge advances in these fields. Sessions focused on the integration of “omics” technologies with function, the influence of immune cells on regeneration, and the role of the extracellular matrix in regeneration. The necessity for basic science studies to enhance fundamental understanding of lung regeneration and to design innovative translational studies was reinforced throughout the conference.