# Next-generation Ligand-dependent Transcriptional Switch Receptors for the Control and Customization of Cell Therapeutics

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $51,752

## Abstract

ABSTRACT
 Cytokine immunotherapeutics and chimeric antigen receptor-T cells (CAR-Ts) carry great potential for
inducing a patient’s own immune system to clear a malignant lesion. Unfortunately, many of these potential
immunotherapies are hindered by poor efficacies and unacceptable toxicities, such as “on-target, off-tumor
effects”, where healthy tissues become unintended CAR-T targets by expressing tumor antigens at low levels.
 In contrast to constitutive CAR expression, inducing a T cell to only express an immunotherapeutic in the
presence of a second tumor antigen adds additional regulation over the cytotoxic response. A recent
development, synthetic Notch (SynNotch) receptor circuits allow for immunotherapeutic expression to be
restricted to tumor sites. However, these receptors do not provide control over the amount of expressed
immunotherapeutic, nor do they allow for regulation of an output’s half-life. The ability to tune the level and
duration of an induced cell-based immunotherapeutic would further improve on the safety of cell-based
immunotherapies and provide a platform for robust tuning of an immunotherapeutic regimen.
 To date in my graduate training, several novel receptor designs that produce distinct levels and half-lives
of transcriptional output in response to a surface-expressed antigen have been engineered. Through receptor
domain modulation, these receptor scaffolds can prompt the delivery of a set amount of output to a set tissue
type, for a set amount of time. In addition, certain novel receptors act as “OR” gates, being activatable by either
ligand or T-cell activation. For this proposal, these receptors will be tested for their ability to induce the expression
of various potential immunotherapeutics, including CARs and cytokines in human primary T-cells, as measured
by ELISA and flow cytometry. In addition, receptors will be tested as part of receptor-CAR positive feedback
circuits for their ability to prime CAR-T cells to better clear a heterogenous tumor by inducing a more sustained
anti-tumor response, both in cell culture and in mouse model.
 The University of California, San Francisco (UCSF) is a leading institution in synthetic immunology, and
its faculty are well experienced in physician-scientist training. As a MD/PhD student in the Roybal lab at UCSF,
I have access to support and collaboration from world-renowned investigators, as well as resources from the
Parker Institute for Cancer Immunotherapy and the Chan Zuckerberg BioHub. In addition to my PhD research,
my training plan includes medical preceptorships with world-class physicians during my graduate training,
additional teaching opportunities through the UCSF School of Medicine, and further clinical training through
UCSF resources, including the UCSF Bridges medical curriculum. Overall, this training proposal seeks to further
develop synthetic receptor circuits as a tool for improving the safety and efficacy of potential immunotherapies
while providing me...

## Key facts

- **NIH application ID:** 10370305
- **Project number:** 5F30CA250247-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Iowis Zhu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370305

## Citation

> US National Institutes of Health, RePORTER application 10370305, Next-generation Ligand-dependent Transcriptional Switch Receptors for the Control and Customization of Cell Therapeutics (5F30CA250247-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10370305. Licensed CC0.

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