Citations

Abstract INTRODUCTION Limited data exist on the utility of plasma biomarkers to predict incident abnormal amyloid positron emission tomography (PET). In this study we evaluate the association of plasma Alzheimer's disease (AD) biomarkers with amyloid PET progression among initially amyloid PET negative (A−) individuals. METHODS We included 290 A−, cognitively unimpaired Mayo Clinic Study of Aging participants. We estimated the association of each baseline plasma biomarker with progression from A− to A+ and with rate of amyloid PET change. RESULTS Interquartile range differences in amyloid beta 42/40, percent phosphorylated tau 217 (%p‐tau217), and Amyloid Probability Score 2 were associated with 1.29 ( P = 0.09), 1.38 ( P < 0.001), and 1.20 ( P = 0.05) increases, respectively, in the hazard of progression from A− to A+ and 0.27 ( P = 0.16), 0.50 ( P = 0.007), and 0.28 ( P = 0.15) Centiloid/year increases, respectively, in annual rate of amyloid PET change. DISCUSSION Plasma %p‐tau217 may be a useful screening tool to enrich for participants with increased likelihood of progressing from normal to abnormal amyloid PET in a primary prevention trial. Highlights Plasma phosphorylated tau 217 was associated with amyloid positron emission tomography progression, negative to positive. The associations were weaker for amyloid beta 42/40 and Amyloid Probability Score 2. Age and apolipoprotein E ε4 carriership were also important predictors. These markers may be useful for enrichment of a primary prevention trial.

Abstract Addressing the limited responsiveness to immune checkpoint blockade (ICB) in human cancers remains a critical challenge. Efforts over the past two decades have primarily focused on enhancing CD8 T cell function and preventing their exhaustion. However, less attention has been given to understanding the molecular mechanisms that contribute to the immunosuppressive tumor microenvironment (TME), which impedes CD8 T cell infiltration and fosters ICB resistance. The TME in ICB-resistant tumors is characterized by Transforming Growth Factor beta (TGF-β) cytokine signaling, leading to a fibrotic extracellular matrix (ECM) and the accumulation of immunosuppressive fibroblasts and myeloid cells. These features hinder CD8 T cell penetration, thereby promoting immune escape. The immune checkpoint molecule B7-H3, overexpressed in ICB-resistant cancers, has been linked to impaired CD8 T cell infiltration and poor prognosis. However, the molecular mechanisms governing B7-H3 function remain poorly understood. We investigated the relationship between B7-H3 gene expression and ICB response using transcriptomic data from two randomized phase 3 trials (IMvigor010 and IMvigor210). Bulk RNAseq data, tissue staining, and spectral flow cytometry were used to characterize the TME composition of B7-H3 high and low tumors. Multi-omic profiling of tumor cell lines with manipulated B7-H3 expression was performed to identify downstream targets of B7-H3. Syngeneic mouse tumor models were used to assess the impact of B7-H3 on tumor growth and antitumor immunity. High B7-H3 expression was associated with shorter overall survival in both IMvigor010 (HR=0.48, 95% CI: 0.33-0.70, p&lt;0.0001) and IMvigor210 trials (HR=0.68, 95% CI: 0.51-0.92, p=0.01). In ICB-refractory cancers, B7-H3 expression correlated with high levels of fibroblasts, collagen deposits, and M2 macrophages. Gene set enrichment analysis revealed a positive association between B7-H3 and TGF-β signaling. Genetic deletion of B7-H3 in tumor cells reduced the surface expression of MMP14, a metalloprotease that activates TGF-β. Pan-cancer analysis identified MMP14 as the gene most correlated with B7-H3 (Pearson r=0.69, p&lt;0.0001). TGF-β activation was reduced by 70% in B7-H3 knockout cells compared to wild-type. Loss of B7-H3 led to MMP14 accumulation in lysosomes, resulting in its degradation. We generated a B7-H3 inhibitor, 5D10, which promotes MMP14 degradation and inhibits TGF-β activation. In humanized B7-H3 mouse models, 5D10 significantly reduced TGF-β activation, enhancing CD8 T cell infiltration and impairing tumor growth. Our research identifies B7-H3 as a driver of immune exclusion and ICB resistance. We describe a novel, receptor-independent mechanism where B7-H3 promotes TGF-β activation via stabilization of MMP14. Targeting B7-H3 represents a strategy to modulate the TME, transforming immune-excluded tumors into immune-inflamed states that may respond better to ICB. Citation Format: Fabrice Lucien, Roxane Lavoie, Jack Korleski, Yohan Kim, Bharath Wootla, Liguo Wang, Ava Farrell, Kelly Harper, Martine Charbonneau, Claire Dubois, Igor Frank, Sounak Gupta, John Cheville, Jacob Orme, Stephen Boorjian, Parash Shah, Eugene Kwon, Sean Park, Haidong Dong. The immune checkpoint molecule B7-H3 is a driver of tumor immune exclusion by mediating TGF-β activation [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B034.

ABSTRACTBackgroundCommercial biomarkers and multiparametric MRI (mpMRI) have been utilized to triage men with elevated prostate specific antigen (PSA) and determine patients most likely to harbor clinically‐significant prostate cancer (csPCa). We studied combinations of mpMRI, PSA‐based and novel extracellular vesicle (EV)‐based biomarkers to determine the optimal pre‐biopsy testing to predict csPCa at biopsy.MethodsMen presenting with elevated PSA (≥ 2 ng/mL) were prospectively enrolled and all men underwent clinically indicated mpMRI and blinded study blood draws to determine PSA, prostate health index (PHI) scoring, and EV serum levels. MRI‐fusion transperineal prostate biopsy was performed in all patients. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and receiver operator characteristic (ROC) curves were constructed. Bootstrapping analysis was performed to provide more accurate assessment of predictive abilities.ResultsUltimately, 175 consecutive men were prospectively enrolled. Median age in the study population was 65 years. Combinations of biomarkers and MRI demonstrated better predictive ability for csPCa on biopsy than individual modalities. Predictive ability was greatest for PHI density (PHID)‐mpMRI with an AUC of 0.86 (95% CI: 0.80–0.92) while combinations of PSA density ‐mpMRI (AUC: 0.81; 95% CI: 0.73–0.89) and STEAP1‐mpMRI (AUC: 0.77; 95% CI: 0.70–0.86) demonstrated similar ability to predict csPCa. The study is limited by small, predominantly white patient cohort and requires external validation.ConclusionsInclusion of prostate density with biomarkers increases prognostic ability for detecting csPCa. EV density can refine prediction of csPCa and in combination with PHID‐mpMRI leads to superior specificity, thereby decreasing unnecessary biopsies.

Abstract INTRODUCTION Early‐onset and late‐onset Alzheimer's disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head‐to‐head comparison of cortical atrophy in EOAD and LOAD, using two large and well‐characterized cohorts (LEADS and ADNI). METHODS We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early‐stage AD), along with cognitively unimpaired participants. RESULTS After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD. DISCUSSION Our findings point to the clinical utility of MRI‐based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment. Highlights Early‐onset Alzheimer's disease (EOAD) and late‐onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia.

PURPOSE Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), two B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in relapsed/refractory multiple myeloma (RRMM). We compare safety, efficacy, and survival among patients with RRMM treated with standard-of-care (SOC) ide-cel or cilta-cel. METHODS Data were from a retrospective chart review of patients with RRMM leukapheresed by December 31, 2022, with the intent to receive SOC ide-cel or cilta-cel at 19 institutions. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type. RESULTS A total of 641 patients were leukapheresed by December 31, 2022, with ide-cel (n = 386) and cilta-cel (n = 255). Five hundred eighty-six patients were infused (n = 350 for ide-cel; n = 236 for cilta-cel) with a median follow-up of 12.6 and 13.0 months for ide-cel and cilta-cel, respectively. After IPTW, patient characteristics were well balanced. Cilta-cel was associated with higher likelihood of grade ≥3 cytokine release syndrome (CRS; odds ratio [OR], 6.80 [95% CI, 2.28 to 20.33]), infections (OR, 2.03 [95% CI, 1.41 to 2.92]), second primary malignancies (OR, 1.77 [95% CI, 0.89 to 3.56]), and delayed neurotoxicity (OR, 20.07 [95% CI, 4.46 to 90.20]). Cilta-cel was also associated with better treatment responses (≥complete response: OR, 2.42 [95% CI, 1.63 to 3.60]), longer progression-free survival (hazard ratio [HR], 0.48 [95% CI, 0.36 to 0.63]), and longer overall survival (HR, 0.67 [95% CI, 0.46 to 0.97]). No associations were observed between therapy type and immune effector cell–associated neurotoxicity syndrome, any CRS, severe cytopenia at days 30 and 90, or nonrelapse mortality. We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time period as Food and Drug Administration approval for cilta-cel (≥March 2022). CONCLUSION Cilta-cel demonstrated superior efficacy and survival, with higher incidence of certain toxicities, compared with ide-cel.

TPS272 Background: Prostate-specific membrane antigen (PSMA)-targeting positron emission tomography (PET) radiopharmaceuticals enable early detection of metastatic and recurrent prostate cancer (PCa). High urinary radioactivity of some PSMA-PET agents can affect interpretation of scans in the pelvic region (prostate/prostate bed [PB]; pelvic lymph nodes [PLN]). 18 F-Piflufolastat and 18 F-flotufolastat are FDA-approved, mainly renally cleared, diagnostic PSMA-PET agents; data suggest 18 F-flotufolastat has lower urinary radioactivity than 18 F-piflufolastat, but no clinical differences have been confirmed by head-to-head intra-patient studies. The present study will directly compare the urinary radioactivity of 18 F-piflufolastat with 18 F-flotufolastat in men with low prostate-specific antigen (PSA) biochemical recurrence (BCR) of PCa after radical prostatectomy (RP). Methods: This multicenter, prospective, intra-patient comparator study will include men (≥ 18 years old) with low PSA (≤ 0.5 ng/mL) BCR of PCa who have had RP ≥ 6 months before enrollment (with undetectable PSA post surgery) and are due to have routine 18 F-piflufolastat PET. Men who have had prior 18 F-piflufolastat PET or salvage therapy, or with conditions affecting urinary output, will be excluded. Eligible patients will undergo 18 F-piflufolastat PET followed by 18 F-flotufolastat PET ≥ 24 hours but ≤ 10 days later. No diuretic will be administered for scanning purposes. Each radiopharmaceutical will be administered as a single intravenous bolus per approved US prescribing information (USPI). Scanning (with the same scanner for both scans) will start 50–90 minutes post injection of 18 F-piflufolastat and 50–70 minutes post injection of 18 F-flotufolastat. Each patient will be their own control. The primary endpoint will be difference in mean standardized uptake value (SUV mean ) between 18 F-piflufolastat and 18 F-flotufolastat as assessed in volumes of interest drawn on the urinary bladder. Secondary endpoints for both agents will include detection rates: at the patient level (overall; by baseline PSA); for local recurrences in PB subregions; and for PLN lesions. For secondary endpoints, PET scans will be interpreted per product-specific USPI by 2 specially trained, blinded, central readers (a third reader will adjudicate disagreements). Safety will be monitored until 24 hours after the second scan. Around 60 men will be screened and ≥ 52 with evaluable PET scans for both agents will be included in the primary analysis. The primary endpoint will be assessed for normality and a difference in SUV mean will be tested using 2-sided paired tests (Wilcoxon signed-rank test [non-normal]; t-test [normal]). All further endpoints, including safety, will be summarized descriptively. The trial has been open for enrollment since 10/24. Clinical trial information: NCT06604442 .

112 Background: We now have more than a decade of experience using Androgen Receptor Pathway Inhibitors (ARPIs) across various disease states of prostate cancer, and the safety of their combination with Lutetium-177–PSMA-617 has been demonstrated in VISION and other large randomized clinical trials. However, real-world data on treatment patterns and outcomes involving combination therapies with 177 Lu-PSMA-617 remain limited. Methods: For this analysis, we utilized the Mayo Clinic Rochester radiopharmaceutical database, a prospectively maintained retrospective database containing all patients who received 177 Lu-PSMA-617 at our institution. We focused on patients who started treatment from March 2022 to March 2023. Patients receiving an ARPI (abiraterone acetate, enzalutamide, apalutamide, or darolutamide) during the course of 177 Lu-PSMA-617 treatment were identified, inclusive of patients who continued using an ARPI prescribed as a prior line of treatment and those who started (i.e., switched) to a new ARPI. Baseline clinicopathologic and imaging characteristics were abstracted and compared using the Mann-Whitney U and Chi-square tests. Best PSA response during treatment was reported as a percent decline from baseline. Survival was calculated from the date of the first cycle of 177 Lu-PSMA-617. PSA50 response and overall survival (OS) outcomes for the two groups (concurrent use of ARPI vs. 177 Lu-PSMA-617 alone) were compared using the Chi-square test and Kaplan-Meier method, respectively. A multivariate Cox regression analysis was performed, including established prognostic factors. Results: An ARPI was prescribed to 106 of the 256 patients (41.4%) starting 177 Lu-PSMA-617 in the interval of March 2022 to March 2023. With regards to baseline characteristics, those receiving an ARPI concurrently with 177 Lu-PSMA-617 had a lower PSA (3.4 vs 29.7 ng/mL, p < 0.001) and a lower frequency of bone (77.4% vs. 87.4%, p = 0.035) and visceral metastases (18.9 vs 34%, p = 0.008) at start of treatment. Median follow-up for the overall cohort (IQR) was 19.1 months (8.7 – 23.6). Patients receiving an ARPI plus 177 Lu-PSMA-617, as compared to 177 Lu-PSMA-617 alone, were more likely to complete all 6 planned doses of treatment (63.2% vs. 48.7%, p < 0.001), though the PSA50 response rate was similar (49.1% vs 47.3%, p = 0.786). Median OS [95% CI] for the overall cohort was 21.3 [16.7 – 25.9] months and significantly longer for those receiving ARPI with 177 Lu-PSMA-617 (NR [NE – NE]) as compared to 177 Lu-PSMA-617 alone (15.3 mo [11.6 – 19.1], p < 0.001). However, on multivariate analysis including known prognostic variables, use of ARPI was not independently associated with improved survival (HR = 1.03 [CI: 0.68 to 1.55], p = 0.891). Conclusions: Patients receiving an ARPI with 177 Lu-PSMA-617 were more likely to complete all 6 cycles of treatment, but no clear differences in survival were observed on multivariate analysis.

341 Background: Specialist clinicians (oncologists, urologists, radiation oncologists) read through free text reports of prostate MRI and biopsy reports to risk stratify patients during initial consultation of localized PCa. This laborious and time-consuming process is repeated for each day during the clinic. Herein, we propose a hybrid stratification framework utilizing a combination of large language model (LLM) and rule-based programming to automate this process. Methods: This retrospective study included patients with localized PCa (2004-2024) presenting to care at Mayo Clinic with at least one positive prostate biopsy and MRI report available. The state-of-the-art LLM – GPT4 – was utilized using a structured zeroshot prompt to extract relevant phenotypic variables (clinical T stage, Gleason patterns, grade group, extent of specimen/cores involved, prostate size/volume) from unstructured MRI and biopsy reports. Using a rule-based algorithm, the extracted variables and PSA at PCa diagnosis were used to categorize each patient into one of the six NCCN risk categories (very low [VL], low [L], favorable intermediate [FInt], unfavorable intermediate [UFInt], high risk (HR), very high risk [VHR]). Prompts were iteratively developed using ~5% of the total dataset and validated on ~10% of the dataset. Final performance was assessed against a held-out expert annotated test dataset using evaluation metrics (accuracy, F1-score, precision, recall). Additionally, manual annotation was conducted by two independent novice reviewers to compare machine annotated and novice-human annotated risk categorization. Results: A total of 397 patients were included in the evaluation. The median age at diagnosis was 64.8 (IQR: 59.7-68.5); majority of the men were White (n: 366; 92%) and non-Hispanic (n: 371; 94%). The most prevalent risk category was UFint (n: 151; 38%) followed by FInt (n: 80; 20.2%), HR (n: 76; 19.1%), VHR (n: 64; 16.1%), L (21: 5.3%), and VL (n: 5; 1.3%). Novice reviewers achieved an accuracy of 79%, precision of 80%, recall of 82% and a F1-score of 0.81. The hybrid stratification framework using GPT4 achieved an accuracy of 89%, precision of 89%, recall of 88% and a F1-score of 0.88. Among 43 errors by GPT4 risk stratification, majority of the errors were due to miscategorization of clinical T-stage (n: 21; 49%) followed by erroneous number of positive cores (n: 13; 30%). However, additional evaluation showed that GPT4 achieved numerically higher performance (accuracy: 90%; precision: 91%; recall: 90%; F1: 0.90) compared to novice reviewers (accuracy: 77%; precision: 89%; recall: 77%; F1: 0.82) for ascertaining clinical T-stage. Conclusions: Large language models exhibited superior performance than novice clinicians for risk stratification in patients with localized PCa. As the next step, we intend to validate our framework for automated risk classification in a prospective manner.

184 Background: We update evidence on mHSPC when new evidence becomes available (PMID: 36862387). ARANOTE trial prompted us to assess the comparative efficacy of darolutamide (DARO) with other ARPi agents in mHSPC using the living network meta-analysis (LNMA). Methods: This LNMA is conducted using the living interactive evidence (LIvE) synthesis framework. Phase III trials assessing systemic treatments in mHSPC are included. Mixed treatment comparisons were made using a frequentist network meta-analysis. P-scores were computed to assess relative treatment rankings with higher values indicating potentially better efficacy. Results: This report of LNMA includes a total 11 trials (12628 patients; 12 unique treatment options) as of October 1 st , 2024. Overall results were consistent with prior updates. Analysis limited to the ARPi trials showed that inhigh volume, abiraterone acetate (AAP)+androgen deprivation therapy (ADT) (HR: 0.46; 95% CI: 0.40-0.53; rank 1), apalutamide (APA)+ADT (0.53; 0.41-0.68; rank 3), DARO+ADT (0.60; 0.44-0.81; rank 4) and enzalutamide (E)+ADT (0.48; 0.41-0.56; rank 2) significantly improved radiographic progression-free survival (rPFS) compared to ADT alone. No statistically significant differences were observed with DARO+ADT compared to AAP+ADT (1.30; 0.94-1.82), APA+ADT (1.14; 0.77-1.67) and E+ADT (1.24; 0.89-1.79). Inlow volume, AAP+ADT (0.48; 0.37-0.63; rank 4), APA+ADT (0.36; 0.22-0.58; rank 3), DARO+ADT (0.30; 0.15-0.60; rank 1) and E+ADT (0.32; 0.25-0.41; rank 2) significantly improved rPFS compared to ADT. E+ADT significantly improved rPFS compared to AAP+ADT (0.67; 0.47-0.96) in low volume. No statistically significant differences were observed with DARO+ADT compared to AAP+ADT (0.62; 0.30-1.30), APA+ADT (0.83; 0.36-1.92) and E+ADT (0.93; 0.45-1.94). In synchronous disease, AAP+ADT (0.58; 0.51-0.67; rank 4), APA+ADT (0.49; 0.39-0.62; rank 2), DARO+ADT (0.59; 0.44-0.79; rank 3) and E+ADT (0.42; 0.36-0.50; rank 1) significantly improved rPFS compared to ADT. E+ADT significantly improved rPFS compared to AAP+ADT (0.73; 0.59-0.89) in synchronous disease. In metachronous disease, DARO+ADT (0.34; 0.17-0.67; rank 1), APA+ADT (0.41; 0.22-0.77; rank 2) and E+ADT (0.44; 0.35-0.57; rank 3) significantly improved rPFS compared to ADT. No statistically significant differences were observed with DARO+ADT compared to APA+ADT (0.83; 0.33-2.08) and E+ADT (0.76; 0.37-1.57) in metachronous disease. The results were consistent for overall survival. Conclusions: Current evidence suggests no significant differences for darolutamide as compared to other ARPi agents. Enzalutamide may be preferred over AAP in low-volume or synchronous disease. Given similar efficacy, choice of ARPi requires careful consideration of patient-specific factors including cost, accessibility and toxicity.