# Adrenergic modulation of cellular immune functions in CAR T cell-induced cytokine release syndrome

> **NIH NIH U01** · JOHNS HOPKINS UNIVERSITY · 2022 · $614,372

## Abstract

Immunotherapy using tumor-directed chimeric antigen receptor (CAR)-expressing T cells (CART) is a rapidly-
emerging, promising cancer therapy that can elicit rapid, durable clinical responses, seen in anti-CD19 CART
(CART19)-treated CD19+ B-cell malignancies. However, CART-evoked severe or fatal immune-related adverse
events (irAE) including cytokine-release syndrome (CRS) are significant clinical barriers and safety concerns
that impede CART use in cancer patients, even with strict patient monitoring and supportive care. Current tools
for mitigating such immunotoxicities/CRS target individual cytokines/receptors (e.g. IL-6R, IL-1Ra, GM-CSF) or
nonspecific immunosuppression, but preventing and treating such toxicity will require better understanding of
cellular/molecular mediators of CART-induced CRS. This project aims to overcome these barriers and enable
more effective interventions against immunotoxicities, and thus more effective CART treatments, building upon
the PIs' novel, potentially translatable findings of a key role of catecholamines (CATs) in shaping CART therapy-
associated immune activation. We found that blocking CAT synthesis both reduced CRS during CART therapy
in mice and also enhanced its tumor eradication, and also found that CAT levels are elevated in patients with
CART-evoked CRS, and correlated with symptoms and IL-6 levels, suggesting CATs contribute to human CRS
pathophysiology. The project's goal is to identify the mechanistic CRS-modulating roles of these novel CAT
actions and their impacts on macrophages and anti-tumor responses, and assess translational potential for
improving CART cancer therapy outcomes using human patient samples. Specific Aims are: 1) Determine the
mediating α1-AR subtype and its role in modulating CART-evoked cytokine release and anti-tumor responses in
vitro and in vivo, based on our finding that CAT-associated cytokine release is mediated by α1-adrenergic
receptors (α1-AR), of as-yet unknown subtype(s). We will identify the α1-AR subtype(s) that mainly mediate(s)
CAT-evoked cytokine production in macrophages and CART, using in vitro co-culture assays and a mouse CART
therapy model via genetic knockout (KO) and knockdown (KD) of α1-AR subtypes. 2) Determine the impact of
myeloid-derived CATs on cytokine release and myeloid function during CART-therapy in vitro and in a mouse
model, by inactivating CAT synthesis in myeloid cells via tyrosine hydroxylase (TH) KO, and assess its impact
on cytokine release and macrophage function in a co-culture assay and in vivo using a LysM-Cre-mediated TH
KO mouse. 3) Assess CAT induction in human patients during CART therapy, and CATs' dual impacts on irAE
and tumor responses, and potential utility of CAT measures and blockers in predicting and preventing CRS, by
quantifying circulating CAT and cytokine levels in patient serum samples collected during CART therapy, and
evaluating correlations of CAT levels with clinical and laboratory CRS indices, anti-tumor res...

## Key facts

- **NIH application ID:** 10304166
- **Project number:** 5U01CA247576-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Renyuan Bai
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $614,372
- **Award type:** 5
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304166

## Citation

> US National Institutes of Health, RePORTER application 10304166, Adrenergic modulation of cellular immune functions in CAR T cell-induced cytokine release syndrome (5U01CA247576-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10304166. Licensed CC0.

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