Immune checkpoint inhibitors (ICIs) are a standard treatment across cancers, yet most patients do not respond, and existing biomarkers generalize poorly across tumor types and therapies. Here we present COMPASS, a pan-ca...Immune checkpoint inhibitors (ICIs) are a standard treatment across cancers, yet most patients do not respond, and existing biomarkers generalize poorly across tumor types and therapies. Here we present COMPASS, a pan-cancer foundation model that predicts immunotherapy response from bulk tumor transcriptomes using a concept bottleneck transformer. COMPASS encodes gene expression through 44 biologically grounded immune concepts representing immune cell states, tumor-microenvironment interaction and signaling pathways. Trained on 10,184 tumors across 33 cancer types, COMPASS achieves better average performance than 22 methods across 16 clinical cohorts spanning seven cancers and six ICIs, improving accuracy by 8.5% and area under the precision-recall curve by 15.7% on average across cohorts. COMPASS generalizes to cancer types and treatments not represented during fine-tuning and may inform indication selection and patient stratification. In survival analyses, patients classified by COMPASS as responders had longer overall survival (hazard ratio = 4.7, P < 0.0001). Personalized response maps connect gene expression to immune concepts, identifying programs associated with response and resistance; in immune-inflamed non-responders, COMPASS highlights programs including TGFβ signaling, endothelial exclusion, CD4 T cell dysfunction and B cell deficiency. COMPASS predicts immunotherapy response and provides hypothesis-generating mechanistic insight for trial design and translational studies.
Aging profoundly remodels the immune system, impairing defense, repair and homeostatic function across tissues. Because the immune system operates in every organ, its deterioration has been proposed to drive or exacerbat...Aging profoundly remodels the immune system, impairing defense, repair and homeostatic function across tissues. Because the immune system operates in every organ, its deterioration has been proposed to drive or exacerbate systemic dysfunction and accelerate overall biological aging, making it an attractive biomarker and target for geroscience-guided trials. Despite this central role, there is no consensus on how to quantify immune aging, especially in clinical trials. Here, we establish a translational framework to identify immune aging biomarkers for this purpose. We define five evaluation criteria for immune aging biomarkers and apply these to candidate biomarkers, discussing their utility in the context of a major international healthspan competition, XPRIZE Healthspan. Metrics encapsulating multidimensional aspects of immune function, inflammaging scores and functional assays performed best against our selection criteria. Finally, we identify promising emerging measures, together with critical gaps that must be addressed to develop reliable, predictive biomarkers of human immune competence. Our framework provides a coherent path toward actionable and clinically meaningful immune aging biomarkers capable of quantifying immune fitness and resilience, and accelerating the clinical translation of geroscience-guided interventions.
Heart failure with reduced ejection fraction carries a poor prognosis. Although guideline-directed medical therapy reduces morbidity and mortality, its real-world utilization is low. Accordingly, we conducted an open-lab...Heart failure with reduced ejection fraction carries a poor prognosis. Although guideline-directed medical therapy reduces morbidity and mortality, its real-world utilization is low. Accordingly, we conducted an open-label randomized trial (POLY-HF) at two centers enrolling a predominantly underserved population to test whether a polypill strategy improves cardiac function in heart failure. Adults with heart failure and left ventricular ejection fraction ≤40% were randomized to a once-daily polypill containing metoprolol succinate (25/50/100/150 mg), spironolactone 12.5 mg and empagliflozin 10 mg, or rapid uptitration of individual guideline-directed medical therapy medications ('enhanced usual care'). Participants also continued treatment with a renin-angiotensin system inhibitor or sacubitril/valsartan as a separate pill. The primary endpoint was ejection fraction as assessed by cardiac magnetic resonance imaging at 6 months. Secondary endpoints included clinical outcomes and adherence. We randomized 212 patients (median age 54 years, 22% female, 54% Black). Follow-up magnetic resonance imaging data were available for 187 (88%) participants who were included in the modified intention-to-treat analysis. Polypill treatment was associated with greater improvement in ejection fraction compared to enhanced usual care (between-group difference, 3.3 percentage points, 95% confidence interval, 0.2-6.4; P = 0.039), meeting the primary outcome. Individuals randomized to the polypill also had a 60% lower rate of heart failure hospitalizations or emergency department visits (adjusted rate ratio, 0.40; 95% confidence interval, 0.18-0.88; P = 0.024). Adherence, assessed by blood concentrations of metoprolol and spironolactone, was higher with polypill treatment than with enhanced usual care (79% versus 54%, P = 0.001). The polypill was well tolerated, with fewer adverse events with polypill treatment as compared to enhanced usual care. A polypill for heart failure was associated with a significant improvement in cardiac function as compared with enhanced usual care. ClinicalTrials.gov registration: NCT04633005 .
Papargyris L, Xu J, Broderick C
… +32 more, Huang A, Gore T, Reynaldi A, Dayananda P, Collins AM, Ascough S, Wong N, Guy J, Song J, Kar S, Bergstrom E, Slater L, Gardener Z, Paterson S, Marjaneh MM, Nichols SJ, Wright VJ, Park MK, McKendry R, Nicholson B, McClain M, Burke TW, Wagstaffe H, Klein J, Levin M, Grifoni A, Woods CW, Davenport MP, Tsang JS, Chain B, Kaforou M, Chiu C
Controlled human influenza infection studies can uniquely interrogate the early immune factors associated with clinical outcome. In this study, 27 healthy volunteers with low strain-specific serum neutralizing antibody l...Controlled human influenza infection studies can uniquely interrogate the early immune factors associated with clinical outcome. In this study, 27 healthy volunteers with low strain-specific serum neutralizing antibody levels were challenged with influenza A/H3N2 virus. Twenty-two became infected, with 18 developing mild-to-moderate symptoms and four remaining asymptomatic. Local and systemic immune profiling revealed innate pathways that engaged more rapidly and to a higher level in symptomatic participants. Earlier monocyte and dendritic cell activation correlated with higher symptom scores but also enhanced natural killer and CD8 T cell activation thereafter. At baseline, peripheral blood mononuclear cells from symptomatic participants were more responsive to in vitro challenge, indicating a predisposition to divergent immunological outcomes at the time of virus exposure that was subsequently modulated by infection. These results show that human innate cell responsiveness is a predeterminant of both symptomatic disease and cellular immune responses known to promote viral clearance, suggesting potential targets for therapeutic intervention if decoupled.
Yang Q, Bidel Z, Canoy D
… +11 more, Zeng G, Cushman WC, Rodgers A, Teo K, Davis BR, Chalmers J, Pepine CJ, Sundström J, Woodward M, Nazarzadeh M, Rahimi K
Blood pressure (BP)-lowering therapy reduces cardiovascular risk, but whether its proportional benefits increase with longer treatment duration remains unclear. We conducted an individual participant-level data meta-anal...Blood pressure (BP)-lowering therapy reduces cardiovascular risk, but whether its proportional benefits increase with longer treatment duration remains unclear. We conducted an individual participant-level data meta-analysis of 51 randomized trials from the Blood Pressure Lowering Treatment Trialists' Collaboration (358,642 participants; median follow-up: 4.2 years). Using Cox proportional hazards models, we estimated time-stratified hazard ratios (HRs) for major cardiovascular events (MACE; fatal or non-fatal stroke, ischemic heart disease or heart failure) across annual follow-up intervals up to more than 5 years, standardized to a 5-mmHg systolic BP reduction. Network meta-analysis examined whether temporal patterns differed across antihypertensive drug classes. Annual MACE incidence was highest during year 1 (3.0% treatment versus 3.6% control), declined during years 1-5 and then rose at more than 5 years (3.1% versus 3.4%). BP lowering reduced MACE risk, with benefits established early and not progressively increasing over time. A 5-mmHg systolic BP reduction was associated with a 12% lower MACE risk in year 1 (HR = 0.88, 95% confidence interval (CI): 0.84-0.91), with modest attenuation thereafter: HRs were 0.88 (0.85-0.92) in years 1-2, 0.94 (0.90-0.98) in years 2-3, 0.87 (0.83-0.92) in years 3-4, 0.97 (0.91-1.03) in years 4-5 and 0.94 (0.87-1.01) at more than 5 years (P for trend = 0.006). Similar patterns occurred across five drug classes. These findings indicate that the relative cardiovascular benefits of BP lowering emerge within months and do not increase over time, suggesting that prioritizing higher-risk individuals for treatment yields greater clinical utility than prolonged treatment in low-risk individuals.
Phillips B, Sanford J, Janve VA
… +22 more, Liu M, Johnson M, Gong K, Bergmann K, Lowery J, Flynn A, Brock W, Montejo BS, Sykora N, Budde J, Mellios N, Papageorgiou G, Sperling RA, Buckley RF, Seto M, Morris JC, Perlmutter JS, Kotzbauer PT, Perrin RJ, Hohman TJ, Ibanez L, Cruchaga C
Detection of Alzheimer's disease (AD) before the development of clinical symptoms is critical for enabling the use of new treatments. Circular RNAs (circRNAs) are highly stable non-coding RNAs enriched in the brain that...Detection of Alzheimer's disease (AD) before the development of clinical symptoms is critical for enabling the use of new treatments. Circular RNAs (circRNAs) are highly stable non-coding RNAs enriched in the brain that can cross the blood-brain barrier. Here, analyzing blood data from 1,221 individuals with AD and healthy individuals, we identified 34 circRNAs associated with AD status. A predictive model including these 34 circRNAs was comparable to plasma phosphorylated Tau-217 (pTau217) in classifying AD based on biomarker-confirmed (amyloid-β and Tau) status and replicated in independent samples from the Knight-Alzheimer Disease Research Center (n = 551: 76 AD, 475 cognitively unimpaired) and preclinical A4 (n = 1,767) cohorts. Classification of biomarker-confirmed status by blood circRNAs (area under the curve (AUC) = 0.945) had a higher predictive ability than plasma pTau217 (AUC = 0.877) and was further improved in the integrated model (circRNA+pTau217 AUC = 0.977). This model showed high AD specificity with low predictive power for Parkinson's disease, frontotemporal dementia, and other neurodegenerative diseases. In the Knight-Alzheimer Disease Research Center discovery cohort, these circRNAs (hazard ratio = 2.92) outperformed pTau217 (hazard ratio = 1.81) and amyloid-positron emission tomography when predicting progression to symptomatic AD. Although prospective validation in larger cohorts is needed, these results propose blood circRNAs as potential biomarkers for AD diagnosis and disease progression.
Garety PA, Edwards CJ, Jafari H
… +17 more, Emsley R, Huckvale M, Rus-Calafell M, Fornells-Ambrojo M, Gumley A, Haddock G, Bucci S, McLeod HJ, McDonnell J, Clancy M, Fitzsimmons M, Ball H, Montague A, Xanidis N, Hardy A, Craig TKJ, Ward T
Multidisciplinary tumor boards integrate longitudinal treatment histories, molecular profiling and rapidly evolving evidence to guide decisions in hematological malignancies, yet access to this level of subspecialty deli...Multidisciplinary tumor boards integrate longitudinal treatment histories, molecular profiling and rapidly evolving evidence to guide decisions in hematological malignancies, yet access to this level of subspecialty deliberation is increasingly uneven. Here we develop HemaGuide, a locally deployable, modular large language model agent that converts unstructured clinical documents into structured case representations, autonomously routes cases to specialized decision modes ('guideline', 'advanced' and 'molecular') and grounds recommendations in disease-specific guideline flowcharts and a clinical decision memory of >2,000 real-world tumor board cases. In expert-blinded benchmarking on 45 high-complexity cases across six foundation models, HemaGuide substantially improved concordance with tumor board decisions. A systematic ablation study across 11 layers confirmed that performance gains were routing-type-dependent, with no single component sufficient across case types. Automated classification of 70 clinically relevant missense variants showed high concordance with expert standards; no oncogenic variant was downgraded to benign and the whole workflow was completed under real-time conditions on commodity hardware with a median latency of 39 s rather than the hours typically required for manual molecular board workflows. In a simulated practice study, agent-assisted resident physicians achieved near-senior concordance and partially outperformed senior physicians in their subspecialty. External validation on 555 independent cases from a second academic center yielded 81.8% concordance across 47 entities, and a prospective 1-month silent trial on 64 consecutive, unselected cases achieved 82.8% concordance. Hallucinations occurred in 2 of 664 evaluated cases (0.3%). Together these data provide evidence that locally deployable, case-grounded large language model agents can deliver auditable clinical decision support across hematological malignancies, with concordance maintained across institutions and under real-time conditions on commodity hardware.
Central nervous system (CNS) tumors are the deadliest cancers in children, highlighting the need for new therapies. The tumor-associated antigens (TAAs) WT1, PRAME and survivin are widely expressed by these tumors, and a...Central nervous system (CNS) tumors are the deadliest cancers in children, highlighting the need for new therapies. The tumor-associated antigens (TAAs) WT1, PRAME and survivin are widely expressed by these tumors, and a manufacturing technique has been developed to target these intracellular TAAs using autologous, nongenetically engineered T cells. Here we therefore conducted ReMIND, an open-label, phase 1 adaptive dose-finding study to determine the safety/feasibility of autologous, systemically administered trivalent T cells targeting WT1, PRAME and survivin in children with CNS tumors. Eligible patients had newly diagnosed diffuse intrinsic pontine glioma without lymphodepletion (arm A, n = 16 enrolled, n = 11 infused) and relapsed/recurrent nonbrainstem CNS malignancies without (arm B, n = 28 enrolled, n = 18 infused) or with (arm C, n = 7 enrolled, n = 4 infused) lymphodepletion. Primary end points were safety, feasibility and maximum tolerated dose determination; secondary end points included preliminary efficacy and immunobiological correlates, including in vivo TAA-T persistence and systemic immune activation. Dose level 3 (8 × 10 cells per m per dose) was determined as the maximum tolerated dose. Treatment was well tolerated with fatigue and headache being the most common adverse events, although two possibly related serious adverse events of tumor swelling occurred. One grade 5 event in a patient with diffuse intrinsic pontine glioma with hydrocephalus, tumor edema and respiratory failure was categorized as a dose-limiting toxicity. Median overall survival for arm A was 13.7 months from diagnosis (range, 6.2-32.0) and median progression-free survival for arms B/C was 5.0 months from infusion (range, 0.5-51.6). Three patients in arms B/C are alive without disease at 31.8, 41.2 and 51.6 months without further treatment, including one complete response. This trial met safety/feasibility primary end points with some preliminary signals of efficacy. ClinicalTrials.gov registration: NCT03652545 .
Byers LA, Cho BC, Cooper AJ
… +28 more, Chiang AC, Han JY, Furqan M, Dowlati A, Morgensztern D, Papadopoulos KP, Choudhury NJ, Vieito M, Bar J, Kim JH, Akerley W, Kim TM, Kim YC, Paz-Ares L, Ahn MJ, Yokouchi H, Meiman D, Munasinghe W, Ogunyankin O, Jahchan N, Wang S, Ferlini C, Robinson RR, Kohlhapp FJ, Palenski T, Rivell G, Hingorani P, Chandana S
Fan X, Zhang L, Gao Z
… +25 more, Han L, Yang P, Wang D, Yu H, Cao Q, Jiang L, Chen X, Zhang X, Cheng X, Chen L, Zhong J, Lv J, Wang W, Dai L, Zhou Z, Shi L, Chen Y, Zhu B, Hu S, Tang H, Chen ZY, Wang W, Chen B, Li H, Shu Y
Re-administration of adeno-associated virus (AAV)-mediated gene therapy remains challenging due to neutralizing antibodies (NAbs) induced by the initial dose. We previously conducted a single-arm trial showing that singl...Re-administration of adeno-associated virus (AAV)-mediated gene therapy remains challenging due to neutralizing antibodies (NAbs) induced by the initial dose. We previously conducted a single-arm trial showing that single-dose administration of AAV-hOTOF gene therapy in individuals with OTOF-related deafness is safe and leads to hearing improvements. Here we initially demonstrate that AAV1-hOTOF re-administration to the contralateral ear in Otof mice with peak serum NAb titers successfully rescued hearing with limited immune activation. After a protocol amendment of our trial, four patients (aged 2.2-3.4 years) with pre-existing NAbs (titers 1:135-1:3,645), who had previously received a single dose of the gene therapy, were enrolled to receive a second dose in the contralateral ear, as part of the ongoing trial, with a follow-up ranging from 26 weeks to 52 weeks. The primary endpoint was the occurrence of dose-limiting toxicities at 6 weeks and secondary endpoints included safety and auditory function. No dose-limiting toxicity occurred within 6 weeks. In the secondary outcomes, the 26-week average auditory brainstem response threshold in the second treated ear improved from >95 dB at baseline to 43 dB, 63 dB, 80 dB and 53 dB in patients 1-4, respectively. Safety assessment showed that all adverse events were grade 1-2, except one grade 3 decreased neutrophil count; no serious adverse events occurred. These data provide preliminary insights on the safety and efficacy of re-administration of AAV1-hOTOF gene therapy in patients with congenital deafness. Longer follow-up and larger cohorts are needed to establish the safety and efficacy of repeated administration of gene therapies. Trial registration no.: ChiCTR2200063181 .
Agweyu A, Mwaniki P, Menon V
… +12 more, Korom R, Isaaka L, Wanyama C, Gill J, Kiptinness S, Adan N, Emmanuel-Fabula M, Riley RD, Archer L, Denniston AK, Liu X, Mateen BA
Rigorous evidence on the performance of large language models (LLMs) in real-world, low-resource clinical settings remains limited. Here we conducted a pragmatic, cluster-randomized trial in 16 primary care facilities in...Rigorous evidence on the performance of large language models (LLMs) in real-world, low-resource clinical settings remains limited. Here we conducted a pragmatic, cluster-randomized trial in 16 primary care facilities in Kenya. Clinical officers were randomized to use the electronic medical record with or without LLM assistance. The primary outcome was an expert-adjudicated composite of treatment failure events experienced within 14 days of enrollment. Between 22 April and 16 July 2025, 9,691 patients were enrolled, overseen by 103 clinical officers (52 in the LLM-assisted arm and 51 in the control arm). Treatment failure occurred in 102/4,693 patients (2.2%) in the intervention arm and 94/4,654 (2.0%) in the control arm (adjusted odds ratio 0.77, 95% confidence interval 0.55 to 1.08, P = 0.13). The primary outcome did not differ significantly between groups. No serious adverse events were judged related to the intervention, and independent review of the adverse events did not identify a safety signal. In this trial, LLM assistance was safe but did not reduce treatment failure within 14 days and any benefit, if present, is probably modest.Pan-African Clinical Trials Registry: 202502499779176.
Kahr PC, Aus dem Siepen F, Lairez O
… +14 more, Donal E, Damy T, Kristen AV, Quarta CC, Mercuri MF, Keppner-Witter S, Herrmann-Keiner E, Tichy M, Michalon A, Grimm J, Nitsch RM, Hock C, Garcia-Pavia P, van der Meer P
In a first-in-human trial (NI006-101), the monoclonal antibody cliramitug, targeting misfolded transthyretin, demonstrated a favorable safety profile and time- and dose-dependent reductions in surrogate markers of cardia...In a first-in-human trial (NI006-101), the monoclonal antibody cliramitug, targeting misfolded transthyretin, demonstrated a favorable safety profile and time- and dose-dependent reductions in surrogate markers of cardiac amyloid burden over the course of 12 months in patients with amyloid transthyretin cardiomyopathy (ATTR-CM). Here we evaluate the long-term safety and efficacy of cliramitug in a subgroup of participants of the NI006-101 trial who continued treatment in a second open-label extension (OLE2) and further explore dose- and time-dependent effects on amyloid depletion, cardiac biomarkers and cardiac structure and function. Twenty-three participants (20 receiving background treatment with tafamidis, all male) entered OLE2 and received a median of 10 additional infusions, increasing the maximum total exposure to 24 infusions and extending the median follow-up to 29.3 months. Thirteen participants initially treated with ≤10 mg kg were up-titrated to 30 mg kg during OLE2. Treatment adherence was high (98%), with no treatment-related serious adverse events or discontinuations. Continued treatment and up-titration in participants with lower prior exposure led to further reductions in cardiac extracellular volume on MRI and tracer uptake on bisphosphonate scintigraphy. Improvements were also observed in NT-proBNP and troponin T levels, left ventricular relaxation, filling pressures and wall thickness. Increases in Kansas City Cardiomyopathy Questionnaire scores suggested potential quality-of-life benefits. Consistent with results from the original trial, cliramitug showed favorable long-term safety and further reductions in cardiac amyloid burden following up-titration to 30 mg kg. These time- and dose-dependent improvements across structural, functional and biomarker endpoints support the therapeutic potential of amyloid-depleting therapy with cliramitug in ATTR-CM. ClinicalTrials.gov: NCT04360434 .
Stroke affects 15 million people annually and leaves 5 million permanently disabled. In the chronic phase (>3 months after stroke), patients often experience persistent sensorimotor deficits and altered body representati...Stroke affects 15 million people annually and leaves 5 million permanently disabled. In the chronic phase (>3 months after stroke), patients often experience persistent sensorimotor deficits and altered body representation, yet rehabilitation delivery remains partial and inconsistent, highlighting an unmet clinical need. Immersive technologies and noninvasive neurostimulation offer potential for scalable, intensive rehabilitation, but clinical evidence supporting multimodal approaches and objective outcome assessments remains limited. In this study, we evaluate the feasibility, clinical efficacy and assessment capabilities of a multimodal platform (MultiSensy) integrating virtual reality with synchronous transcutaneous sensory neurostimulation. Thirty-four patients with chronic stroke were enrolled in a combined pilot study (n = 9) and randomized, 33-day-long feasibility study (n = 25), where MultiSensy intervention was evaluated against conventional rehabilitation. Primary endpoints included motor function assessed by Fugl-Meyer Assessment Upper Extremity (FMA-UE) and Action Research Arm Test (ARAT) and self-body representation assessed by the Body Landmark Test. Secondary outcomes included sensory and functional independence evaluation. Continuous kinematic data were collected to derive objective performance markers. Compared to conventional rehabilitation, MultiSensy resulted in greater motor improvement, reflected by higher FMA-UE (13.17 ± 1.30 versus 7.54 ± 1.48; P = 0.01) and ARAT (8.25 ± 1.96 versus 2.44 ± 1.08; P = 0.029) scores. MultiSensy further improved body self-representation and hand tactile acuity. The platform enabled continuous performance monitoring and extraction of objective kinematic markers that tracked rehabilitation progress. These findings pave the way for larger trials and highlight the potential treatment of multiple patients with fewer physiotherapist visits needed or even home-based sensorimotor rehabilitation. ClinicalTrials.gov identifier: NCT06400823 .