Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma

Meijie Tian; Jun S Wei; Nityashree Shivaprasad; Steven L Highfill; Berkley E Gryder; David Milewski; G Tom Brown; Larry Moses; Hannah Song; Jerry T Wu; Peter Azorsa; Jeetendra Kumar; Dina Schneider; Hsien-Chao Chou; Young K Song; Abdelrahman Rahmy; Katherine E Masih; Yong Yean Kim; Brian Belyea; Corinne M Linardic; Boro Dropulic; Peter M Sullivan; Poul H Sorensen; Dimiter S Dimitrov; John M Maris; Crystal L Mackall; Rimas J Orentas; Adam T Cheuk; Javed Khan

doi:10.1016/j.xcrm.2023.101212

Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma

Cell Rep Med. 2023 Oct 17;4(10):101212. doi: 10.1016/j.xcrm.2023.101212. Epub 2023 Sep 28.

Authors

Meijie Tian¹, Jun S Wei¹, Nityashree Shivaprasad¹, Steven L Highfill², Berkley E Gryder¹, David Milewski¹, G Tom Brown³, Larry Moses², Hannah Song², Jerry T Wu¹, Peter Azorsa¹, Jeetendra Kumar¹, Dina Schneider⁴, Hsien-Chao Chou¹, Young K Song¹, Abdelrahman Rahmy¹, Katherine E Masih⁵, Yong Yean Kim¹, Brian Belyea⁶, Corinne M Linardic⁶, Boro Dropulic⁷, Peter M Sullivan⁸, Poul H Sorensen⁹, Dimiter S Dimitrov¹⁰, John M Maris¹¹, Crystal L Mackall¹², Rimas J Orentas¹³, Adam T Cheuk¹⁴, Javed Khan¹⁵

Affiliations

¹ Genetics Branch, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA.
² Center for Cellular Engineering, Department of Transfusion Medicine, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.
³ Artificial Intelligence Resource, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
⁴ Lentigen Corporation, Miltenyi Bioindustry, 1201 Clopper Road, Gaithersburg, MD 20878, USA.
⁵ Genetics Branch, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
⁶ Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
⁷ Caring Cross, 708 Quince Orchard Road, Gaithersburg, MD 20878, USA.
⁸ Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, 1100 Olive Way, Seattle, WA 98101, USA.
⁹ Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
¹⁰ University of Pittsburgh Department of Medicine, Pittsburgh, PA 15261, USA.
¹¹ Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹² Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, 1100 Olive Way, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101, USA.
¹⁴ Genetics Branch, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA. Electronic address: cheukt@gmail.com.
¹⁵ Genetics Branch, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA. Electronic address: khanjav@mail.nih.gov.

Abstract

Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor receptor 4 (FGFR4) is highly expressed in RMS and lowly expressed in healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen receptor (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as an adoptive T cell treatment for RMS. The 3A11 CAR T cells induced robust cytokine production and cytotoxicity against RMS cell lines in vitro. In contrast, a panel of healthy human primary cells failed to activate 3A11 CAR T cells, confirming the selectivity of 3A11 CAR T cells against tumors with high FGFR4 expression. Finally, we demonstrate that 3A11 CAR T cells are persistent in vivo and can effectively eliminate RMS tumors in two metastatic and two orthotopic models. Therefore, our study credentials CAR T cell therapy targeting FGFR4 to treat patients with RMS.

Keywords: CAR T cell therapy; FGFR4; rhabdomyosarcoma; specific cytotoxicity.

Published by Elsevier Inc.

Publication types

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

MeSH terms

Animals
Cell Line, Tumor
Child
Humans
Immunotherapy, Adoptive
Mice
Receptor, Fibroblast Growth Factor, Type 4 / genetics
Receptor, Fibroblast Growth Factor, Type 4 / metabolism
Receptors, Chimeric Antigen* / genetics
Rhabdomyosarcoma* / drug therapy

Substances

FGFR4 protein, human
Receptor, Fibroblast Growth Factor, Type 4
Receptors, Chimeric Antigen