# Combination antigen sensing engineered T cell for precise recognition and enhanced elimination of solid tumors

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $666,104

## Abstract

Abstract:
The goal of this proposal is to develop an engineered T cell therapy with potential of translation into human
testing. We will develop a clinically optimized combination antigen sensing prime-and-kill circuit T cell for precise
recognition and enhanced elimination of mesothelioma, a rare disease with poor prognosis. The work is built on
our recent progress in T cell engineering and novel tumor antigen discovery: (1) a prime-and-kill dual antigen
AND-gated circuit with fully human components (dubbed as SNIPR for SyNthetic Intramembrane Proteolysis
Receptors) that facilitate clinical translation. (2) A novel tumor specific cell surface antigen ALPPL2 (aka ALPG)
that is expressed in mesothelioma but not any of the normal human tissues except for the placenta. Paired with
the credentialed mesothelioma antigen mesothelin, the ALPPL2 SNIPR → CAR circuit T cell enables precise
temporal and spatial control of T cell activation at the site of the tumor, minimizes on-target off-tumor toxicity,
reduces tonic signaling and T cell exhaustion, and maintains multifunctional T cell states. The circuit design is
modular and flexible and can be induced to locally deliver additional immune modulatory payloads such as
cytokines to further improve efficacy. In addition, our research has shown that SNIPR → CAR circuit T cells are
capable of effectively targeting antigens that are heterogeneously expressed in tumors, a common pitfall for
therapeutic efficacy. We propose to perform translation-enabling studies: (Aim 1) Optimize antibodies for SNIPR
T cell construction, and develop biomarker for patient stratification. (Aim 2) Engineer and evaluate humanized
clinical grade SNIPR → AND logic T cells in vitro and in vivo. (Aim 3) Evaluate SNIPR-engineered prime-and-
kill circuit T cells in killing tumor with heterogeneous target antigen expression. Successful completion of the
project will enable us to move the SNIPR → CAR circuit T cell to translational development and identify via the
biomarker appropriate mesothelioma patients for clinical testing.

## Key facts

- **NIH application ID:** 10651062
- **Project number:** 1R01CA280440-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** BIN LIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $666,104
- **Award type:** 1
- **Project period:** 2023-04-04 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10651062

## Citation

> US National Institutes of Health, RePORTER application 10651062, Combination antigen sensing engineered T cell for precise recognition and enhanced elimination of solid tumors (1R01CA280440-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10651062. Licensed CC0.

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