# Engineering synthetic helper cells that autonomously deliver orthogonal IL-2 to selectively promote therapeutic T cell proliferation in tumors

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $249,969

## Abstract

Project Summary/Abstract
The goal of this collaboration between the Lim/UCSF and June/UPenn IOTN centers is to develop a novel
approach to autonomously and selectively drive proliferation of CAR T cells within a solid tumor. Current clinical
data indicates that strong proliferation is critical for therapeutic success of adoptively transferred T cells1,2. In
solid tumors this is a particularly acute challenge as tumor cells are surrounded by an immunosuppressive
microenvironment that presents multiple barriers to T cell expansion and activity, including suppressive
regulatory T cells that act as sinks for pro-proliferation cytokines3, as well as other suppressor cells and factors
that promote terminal T cell differentiation into an exhausted state4,5. To address these problems, we will combine
the expertise of our two groups: the Garcia Lab (June/UPenn center) has expertise in engineering orthogonal
cytokine/receptor systems, while the Lim Lab (Lim/UCSF center) has expertise in engineering synthetic helper
cells that can autonomously recognize and remodel the tumor microenvironment in a targeted way using
synthetic paracrine cytokine circuits. In this collaboration, we propose to engineer synthetic helper cells that
autonomously produce orthogonal IL-26 in tumors, thereby selectively driving CAR T cell expansion locally. This
collaboration merges approaches from both centers in a synergistic way. If successful, this approach will yield
a way to promote CAR T cell expansion in tumors more effectively, selectively and autonomously than
approaches within the original individual center aims. Our specific aims are to:
Aim 1. Engineer synthetic helper T cells that deliver ortho-IL2 to the tumor micro-environment
Aim 1.1: Engineer mouse ortho-IL-2 helper/killer cell system; test in vitro and in syngeneic tumor models
Aim 1.2: Engineer human ortho-IL-2 helper/killer cell system; test in vitro and in NSG xenograft tumor models
Aim 2: Modulate orthogonal IL-2 receptor signaling to improve and tune cell responses to ortho-IL2.
Systematically alter the signaling domains in the ortho-IL-2 receptor intracellular domain to identify and deploy
variants that increase T cell proliferation and/or minimize exhaustion.

## Key facts

- **NIH application ID:** 10285941
- **Project number:** 3U54CA244438-01S3
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** WENDELL A LIM
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,969
- **Award type:** 3
- **Project period:** 2019-09-24 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285941

## Citation

> US National Institutes of Health, RePORTER application 10285941, Engineering synthetic helper cells that autonomously deliver orthogonal IL-2 to selectively promote therapeutic T cell proliferation in tumors (3U54CA244438-01S3). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10285941. Licensed CC0.

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