# Improving the disposition of antileukemic asparaginase after drug-induced immunotoxicity

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $322,194

## Abstract

Project Summary
Asparaginase (ASNase) is one of the main drugs used for the treatment of pediatric acute lymphoblastic
leukemia (ALL). The most common adverse reaction of ASNase is the development of an immune response that
can compromise drug exposure and lead to worse treatment outcome. Therefore, therapeutic strategies that
prevent or overcome the immune response to ASNase and retain sufficient drug exposure are urgently needed.
PEGylated ASNase (PEG-ASNase) is the first-line agent used for ALL therapy, and it remains prone to
immunotoxicity during treatment.
Our preliminary results showed that: 1) ASNase-induced immune responses can decrease drug exposure
through direct drug neutralization and by accelerating the pharmacokinetic clearance of ASNase; 2) therapeutic
drug levels can be attained after sensitization to PEG-ASNase but may require drug doses higher than in naïve
patients to achieve similar therapeutic effects; 3) there is a higher risk of ASNase hypersensitivity among carriers
of the nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) rs6021191 variant,
which leads to higher expression of this transcription factor involved in the regulation of immune responses; 4)
both IgG and IgE antigen-specific antibodies are involved in the mechanism of ASNase hypersensitivity, which
will be used to facilitate the development of a cell-based approach to monitor PEG-ASNase immunogenicity; and
5) we have established two mouse models of transplantable B cell ALL that can be used to study drug efficacy
and toxicity.
Based on these observations, we hypothesize that (1) pretreatment strategies that can overcome immune
responses to PEG-ASNase by blocking the mediators of hypersensitivity and restoring drug
concentrations can maintain the antileukemic properties of PEG-ASNase. (2) Genetic and
pharmacological inhibition of NFATC2 can prevent or attenuate sensitization to PEG-ASNase. (3) IgG
and/or IgE-mediated binding of peripheral blood cells (PBCs) to PEG-ASNase can be used as a biomarker
of immunotoxicity. We propose three specific aims to test our hypotheses: 1) to determine whether combining
pretreatment drugs that block the mediators of hypersensitivity and PEG-ASNase dose adjustments can
overcome immune responses and retain antileukemic efficacy using two murine models of PEG-ASNase
hypersensitivity and B cell ALL; 2) to determine whether inhibition of the NFAT pathway can prevent sensitization
to PEG-ASNase and maintain antileukemic efficacy; and 3) to determine if sensitized PBCs can be identified
through their binding to fluorescently labeled PEG-ASNase ex vivo using flow cytometry.
The proposed work will identify strategies to overcome, prevent, and monitor the immune response to PEG-
ASNase. The three aims are not interdependent but are logically related with a singular focus on improving PEG-
ASNase therapy. The long-term goal of this project is to improve pediatric ALL survival by overcoming or
preventing the ...

## Key facts

- **NIH application ID:** 10166793
- **Project number:** 5R01CA216815-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Christian Antonio Fernandez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $322,194
- **Award type:** 5
- **Project period:** 2017-06-07 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166793

## Citation

> US National Institutes of Health, RePORTER application 10166793, Improving the disposition of antileukemic asparaginase after drug-induced immunotoxicity (5R01CA216815-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10166793. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*