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

Vipul Bhatia; Nikhil V Kamat; Tiffany E Pariva; Li-Ting Wu; Annabelle Tsao; Koichi Sasaki; Huiyun Sun; Gerardo Javier; Sam Nutt; Ilsa Coleman; Lauren Hitchcock; Ailin Zhang; Dmytro Rudoy; Roman Gulati; Radhika A Patel; Martine P Roudier; Lawrence D True; Shivani Srivastava; Colm M Morrissey; Michael C Haffner; Peter S Nelson; Saul J Priceman; Jun Ishihara; John K Lee

doi:10.1038/s41467-023-37874-2

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

Nat Commun. 2023 Apr 11;14(1):2041. doi: 10.1038/s41467-023-37874-2.

Authors

Vipul Bhatia^#¹, Nikhil V Kamat^#², Tiffany E Pariva^#¹, Li-Ting Wu¹, Annabelle Tsao¹, Koichi Sasaki³, Huiyun Sun¹, Gerardo Javier¹, Sam Nutt¹, Ilsa Coleman¹, Lauren Hitchcock¹, Ailin Zhang¹, Dmytro Rudoy¹, Roman Gulati⁴, Radhika A Patel¹, Martine P Roudier⁵, Lawrence D True⁶, Shivani Srivastava¹, Colm M Morrissey⁵, Michael C Haffner^{1

6

7}, Peter S Nelson^{1

2

4

5

6

7}, Saul J Priceman^{8

9}, Jun Ishihara¹⁰, John K Lee^{11

12

13

14}

Affiliations

¹ Human Biology Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA.
² Division of Medical Oncology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
³ Department of Bioengineering, Imperial College London, 86 Wood Lane, London, W12 0BZ, UK.
⁴ Public Health Sciences Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA.
⁵ Department of Urology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
⁶ Department of Pathology and Laboratory Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.
⁷ Clinical Research Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA.
⁸ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
⁹ Department of Immuno-Oncology, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
¹⁰ Department of Bioengineering, Imperial College London, 86 Wood Lane, London, W12 0BZ, UK. j.ishihara@imperial.ac.uk.
¹¹ Human Biology Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA. jklee5@fredhutch.org.
¹² Division of Medical Oncology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. jklee5@fredhutch.org.
¹³ Department of Pathology and Laboratory Medicine, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA. jklee5@fredhutch.org.
¹⁴ Clinical Research Division, Fred Hutchinson Cancer Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA. jklee5@fredhutch.org.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Animals
Antigens, Neoplasm
Cell Line, Tumor
Humans
Immunotherapy
Interleukin-12
Male
Mice
Oxidoreductases
Prostatic Neoplasms* / pathology
Receptors, Chimeric Antigen*
T-Lymphocytes
Tumor Microenvironment

Substances

Receptors, Chimeric Antigen
Interleukin-12
STEAP1 protein, human
Antigens, Neoplasm
Oxidoreductases

Abstract

Publication types

MeSH terms

Substances

Grants and funding