# Project 3: Modulating Androgen Receptor Signaling to Enhance the Efficacy of CAR T Cell Therapy for Advanced Prostate Cancer

> **NIH NIH P50** · FRED HUTCHINSON CANCER CENTER · 2024 · $280,372

## Abstract

PROJECT SUMMARY
Adoptive cell transfer in the form of chimeric antigen receptor T cell (CART) therapy has revolutionized the
treatment of hematologic malignancies and is slowly making inroads into solid tumors. Challenges to the efficacy
and safety of CARTs in prostate cancer include antigen heterogeneity, an immunologically “cold” tumor
microenvironment, poor persistence, and exhaustion. We have developed a novel CART therapy targeting six
transmembrane epithelial antigen of the prostate 1 (STEAP1) which we found to be expressed more broadly
than prostate-specific membrane antigen (PSMA) in over 87% of lethal metastatic prostate cancers. In preclinical
human-in-mouse and mouse-in-mouse studies, STEAP1 CART demonstrated 1) specificity and antitumor
activity in multiple prostate cancer models with varying levels of STEAP1 antigen density and 2) preliminary
evidence of safety. The STEAP1 CART program has been accepted into the NCI Experimental Therapeutics
(NExT) Program to support clinical translation to a first-in-human study in men with metastatic castration-
resistant prostate cancer (mCRPC). Furthermore, androgens are well known to be immunosuppressive, yet
CART therapy is used without consideration of local androgen concentrations or the sex of the patient. We
present evidence that targeting the androgen receptor is necessary for effective T cell-specific immunotherapy
and enhances the function of adoptive cell therapy products. In addition, we demonstrate that androgen receptor
signaling inhibitors (ARSI) improve antigen presentation and promote T cell function within the prostate tumor
microenvironment. Together, our observations suggest that combining CART therapy with ARSI could improve
therapeutic outcomes in advanced prostate cancer patients. To the best of our knowledge this is the first
combination of preclinical studies and a CART clinical trial to target STEAP1 in advanced prostate cancer
patients.
The goal of this proposal is to understand if we can improve CART function by perturbing androgen receptor
signaling with an ARSI. We hypothesize that we can improve STEAP1 CART cell persistence and function
by combining it with ARSI treatment. We will test this hypothesis in the following Aims: 1) Evaluate the effect
of AR modulation on STEAP1 CART phenotype and function; 2) Investigate whether inflammation and ARSI
impacts safety and toxicity of STEAP1 CART therapy; and 3) Conduct a phase I clinical trial to assess the
feasibility, safety, and efficacy of STEAP1 CART therapy alone and in combination with enzalutamide in men
with STEAP1+ mCRPC.
These studies provide the preclinical framework for understanding how ARSI and/or AR deletion impacts the
function of a novel prostate CART product. Importantly, these studies will provide critical insight into the safety
and toxicity of STEAP1 CART therapy alone or with ARSI and reveal potential therapeutic toxicity.

## Key facts

- **NIH application ID:** 10919790
- **Project number:** 5P50CA097186-23
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** John Kyung Lee
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $280,372
- **Award type:** 5
- **Project period:** 2002-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10919790

## Citation

> US National Institutes of Health, RePORTER application 10919790, Project 3: Modulating Androgen Receptor Signaling to Enhance the Efficacy of CAR T Cell Therapy for Advanced Prostate Cancer (5P50CA097186-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10919790. Licensed CC0.

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