ARPA-H Backs a Precision-Immunology Platform for the ICU
An award of up to $41.4 million will support a Stanford-led effort to measure changing immune states in critical illness and use them to guide treatment. The scientific premise is gaining support, but turning immune profiles into reliable bedside decisions remains a major challenge.
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A Stanford Medicine team led by Purvesh Khatri has received an award of up to $41.4 million from the Advanced Research Projects Agency for Health (ARPA-H) to develop an immune-monitoring and treatment-guidance system for critically ill patients. Inflammatix, which announced its role on October 8, will serve as the team’s commercialization collaborator and bedside-platform developer.
The project, called IMPRINT—Immune Mapping and Perturbation for Real-time Identification and Treatment—is part of ARPA-H’s broader CIRCLE program. The team plans to combine immune and organ-specific measurements with electronic health record data in a mechanistic “digital twin” intended to model a patient’s evolving illness and help identify potential therapies. ARPA-H describes the Stanford project as including transcriptomic markers and an organoid-based system for testing model predictions. Inflammatix says it will develop an investigational, rapid whole-blood readout that can be repeated as a patient’s condition changes. (ARPA-H award description; Inflammatix announcement) ARPA-H Sweeney at Linked In.
ARPA-H CIRCLE is designed for critical illness broadly, including sepsis, trauma and other conditions—not sepsis alone. Its central premise is that patients who appear to have the same clinical syndrome may have substantially different immune biology, and may therefore respond differently to immune-modulating treatments. The program’s stated goal is to develop integrated systems for measuring immune function, modeling its course and identifying potential points for intervention. ARPA-H
Sepsis is a syndrome with varied immune responses
Sepsis is often discussed as though it were a single disease, but its clinical definition describes organ dysfunction arising from a dysregulated response to infection. The infection’s source and organism matter; so does the host response. Some patients show prominent inflammatory activation, while others show features of impaired immune function. These patterns can overlap, and a patient’s immune state can change over time.
That heterogeneity has complicated trials of therapies aimed at the host response. A treatment that helps one biologic subgroup might have little effect—or cause harm—in another. Averages across a broad sepsis population can obscure those differences.
Research over the past decade has begun to define these subgroups. In a 2016 prospective study, Davenport and colleagues identified two blood gene-expression signatures, one of which was associated with immunosuppressive features and higher short-term mortality. A 2017 study by Scicluna and colleagues identified four genomic endotypes across sepsis cohorts; one was consistently associated with worse outcomes. These studies established that the host response could be classified in biologically meaningful ways, although they did not by themselves establish treatment-selection rules for routine care. (Davenport et al., Lancet Respiratory Medicine, 2016; Scicluna et al., Lancet Respiratory Medicine, 2017) PubMed
Clinical data have also been used to define sepsis phenotypes. In a 2019 JAMA study, Seymour and colleagues identified four groups—alpha, beta, gamma and delta—with differing patterns of organ dysfunction, inflammatory biomarkers and mortality. Simulations suggested that variation in phenotype frequency could affect whether a clinical trial appeared to show benefit, harm or no effect. The authors emphasized that further research was needed before the classifications could guide clinical care. (Seymour et al., JAMA, 2019) PubMed
A more recent effort, the Hi-DEF framework, shifts attention toward the degree of dysregulation in myeloid and lymphoid immune compartments. In an analysis drawing on more than 7,000 samples from 37 cohorts, those dimensions were associated with severity and mortality across sepsis and other critical illnesses. The framework is relevant to CIRCLE’s broader ambition: to characterize immune dysfunction in ways that may apply across diagnoses rather than relying solely on the label that brought a patient to the ICU. The framework remains a research tool, and its authors describe it as a potential aid to understanding and treatment development. (Moore et al., Nature Medicine, 2025) PubMed
A clinical trial offers an early treatment signal
The case for immune-guided therapy is no longer based only on observational studies. In the 2026 ImmunoSep randomized clinical trial, 276 adults with sepsis were assigned to biomarker-guided immunotherapy or placebo. Patients classified as having macrophage activation-like syndrome received anakinra; those classified as having sepsis-induced immunoparalysis received interferon gamma.
By day 9, the prespecified improvement in organ dysfunction, measured by the SOFA score, occurred in 35.1% of the precision-immunotherapy group and 17.9% of the placebo group. The trial did not find a statistically significant difference in 28-day mortality. The result is an important proof of concept for matching immune-directed treatment to measured biology, while leaving open questions about patient selection, the biomarker thresholds, safety and effects on outcomes that matter beyond short-term organ function. (Giamarellos-Bourboulis et al., JAMA, 2026) PubMed
From immune measurement to bedside decisions
IMPRINT’s challenge will be to make the proposed measurements fast and dependable enough to inform care while the patient’s condition is changing. The digital twin will also need to provide recommendations that clinicians can interpret and that prospective studies can test. A biological pattern associated with poor outcomes is not automatically a marker that predicts benefit from a specific therapy.
For now, the award supports development and testing of an investigational platform. It does not establish a new clinical standard for sepsis treatment. Antibiotics, source control and organ support remain the foundations of sepsis care; immune-modulating therapies guided by these emerging classifications require further clinical validation.
The program’s larger bet is that repeated immune measurement, combined with clinical data and mechanistic modeling, could help move critical care from syndrome-based categories toward treatment decisions informed by a patient’s biology. The ImmunoSep results suggest that this is a testable clinical strategy. CIRCLE will now attempt to build the measurement and modeling infrastructure to pursue it across critical illness.
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