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A Drug Development Tool for Assessing CRS and Neurotoxicity in Immunotherapy

Award Number: R21EB039495
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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A Drug Development Tool for Assessing CRS and Neurotoxicity in Immunotherapy - Abstract T cell–engaging bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T cell therapies have transformed cancer treatment but carry serious safety risks. Cytokine release syndrome (CRS) is a common inflammatory response driven by therapeutic T cell activity, while immune effector cell–associated neurotoxicity syndrome (ICANS) is a less frequent but life-threatening downstream complication. ICANS occurs when CRS- associated cytokines reach the brain, disrupting the blood–brain barrier (BBB), activating endothelium, causing fibrinogen leakage, and triggering neuroinflammation. Survivors can experience lasting cognitive impairment or death. Current preclinical models fail to predict CRS magnitude or ICANS risk for individual patients, limiting safe dose selection and stratification in early-phase clinical trials. This project aims to develop a tandem-chip microphysiological system (MPS) that models CRS-to-ICANS progression using patient blood. The upstream µSiM-CRS (microphysiological system featuring a silicon membrane) will generate CRS plasma, which will be routed to a cytokine-responsive neurovascular unit (NVU) chip, recapitulating hallmark features of ICANS. This Drug Development Tool (DDT) will enable mechanistic, patient-specific safety profiling to guide immunotherapy development and support future clinical decision- making. Because systemic inflammation–driven brain injury also occurs in sepsis, acute lung injury, and postoperative delirium, this platform has broader utility in understanding, preventing, and developing therapeutics for inflammation-induced neurological complications. This work builds on established MPS technologies developed at Rochester. The µSiM platform, a silicon nanomembrane-enabled modular tissue chip, has been validated for BBB modeling and barrier function studies. Integrated photonic biosensors developed by our team enable real-time cytokine detection in tissue chips. We will combine these technologies to create an automated CRS/ICANS simulator. In Aim 1, we will develop the µSiM-CRS to generate CRS plasma from whole blood exposed to BsAbs known to trigger CRS. We will incorporate endothelial cells to enhance biological fidelity and use in situ biosensing to quantify cytokine release, validating against conventional assays with blood from healthy donors. In Aim 2, we will adapt the µSiM-NVU to detect BBB injury downstream of CRS. Integrated photonic sensors will report cytokine and fibrinogen translocation. Barrier permeability, astrocyte activation, and neutrophil infiltration will be quantified. Initial “walk-over” experiments using CRS plasma directly will be followed by full microfluidic integration of the tandem-chip concept. A successful project will establish the µSiM-CRS-ICANS as a high-throughput platform for assessing immunotherapy neurotoxicity risk. This effort aligns with recent FDA initiatives to transition away from animal testing for biologics and will position this technology for future regulatory qualification and clinical translation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $226,625 )
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	8/20/2026	NEW	$226,625
														Subtotal = $226,625

Grand Total All Awards = $226,625

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A Drug Development Tool for Assessing CRS and Neurotoxicity in Immunotherapy

Award Number: R21EB039495

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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