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Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy

delete2023-04-11
delete38
delete
OA
AI
V
Vipul Bhatia
N
Nikhil Kamat
T
Tiffany E. Pariva
L
Liting Wu
A
Annabelle Tsao
K
Koichi Sasaki
H
Huiyun Sun
G
Gerardo Javier
W
W. Sam Nutt
I
Ilsa M. Coleman
L
Lauren Hitchcock
A
Ailin Zhang
D
Dmytro Rudoy
R
Roman Gulati
R
Radhika A. Patel
M
Martine P. Roudier
L
Lawrence D. True
S
Shivani Srivastava
C
Colm Morrissey
M
Michael C. Haffner
P
Peter S. Nelson
S
Saul J. Priceman
J
Jun Ishihara *
J
John K. Lee *
DOI：10.1038/s41467-023-37874-2delete
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Abstract

Abstract

En 中文
Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen for therapeutic targeting in prostate cancer. Here, we report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading. Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a highly enriched cell surface antigen expressed in prostate cancer. Here the authors describe the design of STEAP1 directed CART cells and show their antitumor activity in preclinical models of prostate cancer, also in combination with a collagen binding domain-IL-12 fusion cytokine.
Keywords:
RECOMBINANT HUMAN INTERLEUKIN-12
6-TRANSMEMBRANE EPITHELIAL ANTIGEN
GENE-THERAPY
STEM-CELLS
IN-VITRO
MEMORY
PROGRESSION
ANTITUMOR
SURVIVAL
MODEL
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Key information extracted from the uploaded paper, including a brief overview, abstract, background, key highlights, visual analysis, and future outlook.

Journal

Nature Communications cover
Nature Communications
IF:
15.7
Papers:
9.2W
Citations:
91.2W

Organization

U
University of Washington
Scholars:
8.0W
Papers: 7.0W
Citations: 12.5W
F
Fred Hutchinson Cancer Center
Scholars:
1.2W
Papers: 9.3K
Citations: 18
I
Imperial College London
Scholars:
8.3W
Papers: 7.3W
Citations: 11.1W
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