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

被引：67

作者：

Bhatia, Vipul ^{[1
]}

Kamat, Nikhil V. ^{[2
]}

Pariva, Tiffany E. ^{[1
]}

Wu, Li-Ting ^{[1
]}

Tsao, Annabelle ^{[1
]}

Sasaki, Koichi ^{[3
]}

Sun, Huiyun ^{[1
]}

Javier, Gerardo ^{[1
]}

Nutt, Sam ^{[1
]}

Coleman, Ilsa ^{[1
]}

Hitchcock, Lauren ^{[1
]}

Zhang, Ailin ^{[1
]}

Rudoy, Dmytro ^{[1
]}

Gulati, Roman ^{[4
]}

Patel, Radhika A. ^{[1
]}

Roudier, Martine P. ^{[5
]}

True, Lawrence D. ^{[6
]}

Srivastava, Shivani ^{[1
]}

Morrissey, Colm M. ^{[5
]}

Haffner, Michael C. ^{[1
,6
,7
]}

Nelson, Peter S. ^{[1
,2
,4
,5
,6
,7
]}

Priceman, Saul J. ^{[8
,9
]}

Ishihara, Jun ^{[3
]}

Lee, John K. ^{[1
,2
,6
,7
]}

机构：

[1] Fred Hutchinson Canc Ctr, Human Biol Div, 1100 Fairview Ave N, Seattle, WA 98109 USA

[2] Univ Washington, Div Med Oncol, 1959 NE Pacific St, Seattle, WA 98195 USA

[3] Imperial Coll London, Dept Bioengn, 86 Wood Lane, London W12 0BZ, England

[4] Fred Hutchinson Canc Ctr, Publ Hlth Sci Div, 1100 Fairview Ave N, Seattle, WA 98109 USA

[5] Univ Washington, Dept Urol, 1959 NE Pacific St, Seattle, WA 98195 USA

[6] Univ Washington, Dept Pathol & Lab Med, 1959 NE Pacific St, Seattle, WA 98195 USA

[7] Fred Hutchinson Canc Ctr, Clin Res Div, 1100 Fairview Ave N, Seattle, WA 98109 USA

[8] City Hope Natl Med Ctr, Dept Hematol & Hematopoiet Cell Transplantat, 1500 East Duarte Rd, Duarte, CA 91010 USA

[9] City Hope Natl Med Ctr, Beckman Res Inst, Dept Immunooncol, 1500 East Duarte Rd, Duarte, CA 91010 USA

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

关键词：

RECOMBINANT HUMAN INTERLEUKIN-12; 6-TRANSMEMBRANE EPITHELIAL ANTIGEN; GENE-THERAPY; STEM-CELLS; IN-VITRO; MEMORY; PROGRESSION; ANTITUMOR; SURVIVAL; MODEL;

D O I：

10.1038/s41467-023-37874-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：23

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