Cancer Cell. 2019 Feb 11;35(2):221-237.e8. doi: 10.1016/j.ccell.2019.01.002.
Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells.
Du H1, Hirabayashi K1, Ahn S2, Kren NP3, Montgomery SA4, Wang X5, Tiruthani K6, Mirlekar B3, Michaud D7, Greene K8, Herrera SG1, Xu Y1, Sun C1, Chen Y1, Ma X1, Ferrone CR5, Pylayeva-Gupta Y3, Yeh JJ9, Liu R10, Savoldo B11, Ferrone S5, Dotti G12.
1
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
2
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
3
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
4
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
5
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
6
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
7
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA.
8
Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
9
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Surgery, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
10
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USA.
11
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599, USA.
12
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: gdotti@med.unc.edu.
The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts. |
