# Targeting GARP-TGFbeta for Immunotherapy of Non-Small Cell Lung Cancer

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $641,336

## Abstract

PROJECT SUMMARY
Although immune checkpoint blockade (ICB) has become a standard cancer therapy, most patients – including
~70% of those with non-small cell lung cancer (NSCLC) – fail to respond to ICB. Accumulation of transforming
growth factor-β (TGFβ) in the tumor microenvironment (TME) can drive immune dysfunction by inducing
regulatory T cells (Tregs) and inhibiting effector CD8+ T cells, resulting in ICB resistance. However, given the
pleotropic, multifunctional nature of TGFβ, systemic inhibition has been clinically challenging with multiple side
effects. Thus, developing translatable approaches to inhibit TGFβ within the TME is of paramount importance.
Glycoprotein-A repetitions predominant (GARP), encoded by LRRC32, is a cell surface, non-signaling, docking,
and activating receptor for latent TGFβ that is highly expressed in cancer cells (including lung cancer), activated
Tregs, and platelets. We discovered that genetic deletion of Lrrc32 in Tregs or platelets enhanced protection
against mouse models of inflammation-associated colorectal cancer and colon cancer. We validated GARP as
a therapeutic target by generating a monoclonal antibody against it (called PIIO-1). PIIO-1 diminishes TGFβ
signaling in the TME specifically due to its selective ability to recognize GARP on Tregs but not platelets. To test
the translational capacity of PIIO-1, we generated a human LRRC32 knock-in mouse that globally replaces the
murine extracellular components of GARP with the human sequence – this allows us to study safety and efficacy
of PIIO-1 in murine models. We found that PIIO-1 has single agent activity against multiple cancer models and
can promote CD8+ T cell function in vivo, as evidenced by reduced CD8+ T cell exhaustion and increased CXCR3+
CD8+ T effector function in the TME. Prolonged exposure to PIIO-1 did not induce platelet-related toxicity. Finally,
we found that PIIO-1 improves therapeutic efficacy of PD-1 blockade against murine models of lung cancer.
Given these exciting discoveries, we hypothesize that disrupting the GARP-TGFβ axis within the TME using
our anti-GARP antibody PIIO-1 will augment the anti-tumor immunity of CD8+ T cells and overcome ICB
resistance in patients with NSCLC. We will test this hypothesis with the following specific aims: Aim 1. Define
how GARP inhibits CD8+ T cell differentiation programming and effector function in the TME. Aim 2. Evaluate
and characterize PIIO-1 as an immunotherapeutic agent against preclinical models of NSCLC, alone or in
combination with ICB, to support the development and initiation of a potentially best-in-class anti-GARP
antibody phase I clinical trial.
This study will address the role of our novel anti-GARP antibody in therapeutic efficacy against NSCLC and
elucidate the mechanisms by which it regulates CD8+ T cell programming and effector function. It has the
potential to overcome risks associated with systemic inhibition of TGFβ pathway and produce a novel agent for
cancer immunothera...

## Key facts

- **NIH application ID:** 10882206
- **Project number:** 1R01CA282501-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Zihai Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $641,336
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882206

## Citation

> US National Institutes of Health, RePORTER application 10882206, Targeting GARP-TGFbeta for Immunotherapy of Non-Small Cell Lung Cancer (1R01CA282501-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10882206. Licensed CC0.

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