Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells

Hongwei Du; Koichi Hirabayashi; Sarah Ahn; Nancy Porterfield Kren; Stephanie Ann Montgomery; Xinhui Wang; Karthik Tiruthani; Bhalchandra Mirlekar; Daniel Michaud; Kevin Greene; Silvia Gabriela Herrera; Yang Xu; Chuang Sun; Yuhui Chen; Xingcong Ma; Cristina Rosa Ferrone; Yuliya Pylayeva-Gupta; Jen Jen Yeh; Rihe Liu; Barbara Savoldo; Soldano Ferrone; Gianpietro Dotti

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

Cancer Cell. 2019 Feb 11;35(2):221-237.e8. doi: 10.1016/j.ccell.2019.01.002.

Authors

Hongwei Du¹, Koichi Hirabayashi¹, Sarah Ahn², Nancy Porterfield Kren³, Stephanie Ann Montgomery⁴, Xinhui Wang⁵, Karthik Tiruthani⁶, Bhalchandra Mirlekar³, Daniel Michaud⁷, Kevin Greene⁸, Silvia Gabriela Herrera¹, Yang Xu¹, Chuang Sun¹, Yuhui Chen¹, Xingcong Ma¹, Cristina Rosa Ferrone⁵, Yuliya Pylayeva-Gupta³, Jen Jen Yeh⁹, Rihe Liu¹⁰, Barbara Savoldo¹¹, Soldano Ferrone⁵, Gianpietro Dotti¹²

Affiliations

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.

Abstract

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.

Keywords: 4-1BB; B7-H3; CD28; PD-1/PD-L1; chimerc antigen receptor; neuroblastoma; ovarian cancer; pancreatic cancer; solid tumors.

Publication types

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

MeSH terms

Animals
B7 Antigens / genetics
B7 Antigens / immunology*
B7-H1 Antigen / immunology
CD28 Antigens / immunology
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / immunology
Carcinoma, Pancreatic Ductal / pathology
Carcinoma, Pancreatic Ductal / therapy*
Cell Line, Tumor
Coculture Techniques
Female
Humans
Immunotherapy, Adoptive / adverse effects
Immunotherapy, Adoptive / methods*
Male
Mice, Inbred C57BL
Neuroblastoma / genetics
Neuroblastoma / immunology
Neuroblastoma / pathology
Neuroblastoma / therapy*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / immunology
Ovarian Neoplasms / pathology
Ovarian Neoplasms / therapy*
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / immunology
Pancreatic Neoplasms / pathology
Pancreatic Neoplasms / therapy*
Receptors, Chimeric Antigen / genetics
Receptors, Chimeric Antigen / immunology*
Signal Transduction
Tumor Burden
Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology
Xenograft Model Antitumor Assays

Substances

B7 Antigens
B7-H1 Antigen
CD274 protein, human
CD276 protein, human
CD28 Antigens
Cd274 protein, mouse
Cd276 protein, mouse
Receptors, Chimeric Antigen
TNFRSF9 protein, human
Tnfrsf9 protein, mouse
Tumor Necrosis Factor Receptor Superfamily, Member 9

Abstract

Publication types

MeSH terms

Substances

Grants and funding