# Development of a novel checkpoint inhibitor-TGF beta combination therapy to reverse immune suppression and increase survival rates in advanced colorectal cancer patients

> **NIH NIH R43** · SYNTHIS THERAPEUTICS, INC. · 2020 · $210,000

## Abstract

SYNTHIS SBIR Ph I PROJECT SUMMARY/ABSTRACT
Colorectal cancer (CRC) is the 3rd most common cancer and the 2nd leading cause of cancer deaths in the US.
Approximately 15-20% of CRC patients have high microsatellite instability (MSI-H). Although the FDA-
approved immune checkpoint, anti-PD1 antibodies, nivolumab and pembrolizumab are effective in MSI-H
CRCs, patient response rates are a modest 28-35%. The remaining 80% of CRC patients that are
microsatellite stable (MSS) do not respond to anti-PD1/PDL1. With considerable room to improve in both
populations, new combination IO treatments should 1) boost responses in MSI-H patients, and/or 2) offer new
treatment options for the majority of checkpoint-resistant CRC patients with immunosuppressed “cold” tumors.
TGF-β is an immuno-suppressive cytokine, with elevated levels in late stage CRC patients that cripple the
adaptive immune system and decrease survival rates. In murine colon cancer models, blockade of the PD1
pathway led to a compensatory increase in TGF-β signaling, while blockade of both pathways led to tumor
regression. Because historically systemic TGF-β blockade cause an array of significant issues, including host
toxicity, novel TGF-β therapies are required to convert IO therapy-resistant “cold” CRCs into immunogenic
“hot” tumors to drive tumor clearance. At Synthis, we are developing a novel, more aggressive checkpoint
therapy combined with TGF-β inhibition (named: PTA) to eradicate CRC. In Aim 1, we will demonstrate that
PTA reverses immune-suppression in vitro, and restores pathways critical for tumor clearance, such as IFN-γ
expression and cytotoxic T cell mediated tumor killing. In Aim 2, we will test PTA in colon cancer models in
vivo, using the humanized HuGEMM PD1 mouse model, which expresses human PD1 on T cells. PTA will be
tested in an in vivo PD assay to establish the appropriate dose range to use in efficacy studies. We will then
test PTA for efficacy in the MC38 colon cancer model in vivo, as well as harvest tumor infiltrating lymphocytes
(TILs) to investigate the effect of PTA on immune cell infiltration and/or activation. The ultimate goal of PTA is
to convert “cold” CRC tumors into immune infiltrated “hot” tumors and increase patient survival rates. New
combination studies with anti-PD1 plus IO therapies are in high demand. Because CRC patients are resistant
to single anti-PD1 therapies, a novel, more aggressive IO approach is required. With a predicted CRC global
market size of $11B in 2022, PTA will be positioned as a single IO therapy that will eliminate two validated
immuno-suppressive pathways to treat CRC patients and increase patient survival.

## Key facts

- **NIH application ID:** 10129581
- **Project number:** 3R43CA239840-01A1S1
- **Recipient organization:** SYNTHIS THERAPEUTICS, INC.
- **Principal Investigator:** Dori A Thomas-Karyat
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $210,000
- **Award type:** 3
- **Project period:** 2019-08-01 → 2021-03-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129581

## Citation

> US National Institutes of Health, RePORTER application 10129581, Development of a novel checkpoint inhibitor-TGF beta combination therapy to reverse immune suppression and increase survival rates in advanced colorectal cancer patients (3R43CA239840-01A1S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129581. Licensed CC0.

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