# First in Human Phase I/II clinical trial of ONC-392: Preserving CTLA-4 immune tolerance checkpoint for safer and more effective cancer immunotherapy

> **NIH NIH R44** · ONCOC4, INC. · 2021 · $1,000,000

## Abstract

Summary
A major paradigm in cancer immunotherapy is to use checkpoint inhibitors to break regulatory mechanisms
that guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example to
establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but
high toxicity. Our preclinical study demonstrate that this outcome is predicated by inactivating the CTLA-4
checkpoint that plays important role in immune tolerance protecting body against autoimmune diseases.
Importantly, our studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer
immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4
antibodies. The irAE is attributable to inactivation of CTLA-4 checkpoint, while the CITE is effective through
selective depletion of regulatory T cells (Treg) in tumor microenvironment.
We hypothesize that a safer and more effective CTLA-4-targeting immunotherapy should preserve rather
than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg-depletion in
tumor microenvironment.
In preparation to test this ground-breaking hypothesis clinically, we have generated a new generation of anti-
CTLA-4 antibodies that preserving CTLA-4 immune checkpoint by avoiding lysosomal degradation of CTLA-4.
The new antibody, ONC-392, has dramatically lower irAEs in humanized mouse model and significantly higher
potent activity in depleting tumor-infiltrating regulatory T cells, resulting in more effective CITE. We have
conducted IND-enabling studies, including GMP-grade manufacturing and GLP toxicity in non-human primate.
We have also sought FDA feedback on our clinical plan through a pre-IND meeting. These progresses
allowed us to propose a Fast Track Phase 1/2 SBIR application to determine safety and efficacy of ONC-392 in
human cancer patients. With the support of the SBIR grant, we will carry out an open label Phase I/II clinical
study to test the safety, pharmacokinetics (PK), and efficacy of ONC-392 as a single agent and in
combination with Pembrolizumab in advanced solid tumors and non-small cell lung cancer patients.
Our proposed study will not only confirm safety of ONC-392, but also provide clinical proof-of-concept data for
our new paradigm of CTLA-4 targeting cancer immunotherapy.

## Key facts

- **NIH application ID:** 10303238
- **Project number:** 4R44CA250824-02
- **Recipient organization:** ONCOC4, INC.
- **Principal Investigator:** Kai He
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,000,000
- **Award type:** 4N
- **Project period:** 2020-04-03 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10303238

## Citation

> US National Institutes of Health, RePORTER application 10303238, First in Human Phase I/II clinical trial of ONC-392: Preserving CTLA-4 immune tolerance checkpoint for safer and more effective cancer immunotherapy (4R44CA250824-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10303238. Licensed CC0.

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