B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheresResearch in context
Dean Nehama,
Natalia Di Ianni,
Silvia Musio,
Hongwei Du,
Monica Patané,
Bianca Pollo,
Gaetano Finocchiaro,
James J.H. Park,
Denise E. Dunn,
Drake S. Edwards,
Jeffrey S. Damrauer,
Hannah Hudson,
Scott R. Floyd,
Soldano Ferrone,
Barbara Savoldo,
Serena Pellegatta,
Gianpietro Dotti
Affiliations
Dean Nehama
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
Natalia Di Ianni
Laboratory of Immunotherapy of Brain Tumors, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Silvia Musio
Laboratory of Immunotherapy of Brain Tumors, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Hongwei Du
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
Monica Patané
Unit of Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Bianca Pollo
Unit of Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Gaetano Finocchiaro
Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
James J.H. Park
Department of Radiation Oncology, Duke University Health System, Durham, NC, USA
Denise E. Dunn
Department of Radiation Oncology, Duke University Health System, Durham, NC, USA
Drake S. Edwards
Department of Radiation Oncology, Duke University Health System, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University Health System, Durham, NC, USA
Jeffrey S. Damrauer
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
Hannah Hudson
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
Scott R. Floyd
Department of Radiation Oncology, Duke University Health System, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University Health System, Durham, NC, USA
Soldano Ferrone
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Barbara Savoldo
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA
Serena Pellegatta
Laboratory of Immunotherapy of Brain Tumors, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Correspondence to: S. Pellegatta, Laboratory of Immunotherapy of Brain Tumors, Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.
Gianpietro Dotti
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA; Correspondence to: G. Dotti, Department of Microbiology and Immunology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
Background: The dismal survival of glioblastoma (GBM) patients urgently calls for the development of new treatments. Chimeric antigen receptor T (CAR-T) cells are an attractive strategy, but preclinical and clinical studies in GBM have shown that heterogeneous expression of the antigens targeted so far causes tumor escape, highlighting the need for the identification of new targets. We explored if B7-H3 is a valuable target for CAR-T cells in GBM. Methods: We compared mRNA expression of antigens in GBM using TCGA data, and validated B7-H3 expression by immunohistochemistry. We then tested the antitumor activity of B7-H3-redirected CAR-T cells against GBM cell lines and patient-derived GBM neurospheres in vitro and in xenograft murine models. Findings: B7-H3 mRNA and protein are overexpressed in GBM relative to normal brain in all GBM subtypes. Of the 46 specimens analyzed by immunohistochemistry, 76% showed high B7-H3 expression, 22% had detectable, but low B7-H3 expression and 2% were negative, as was normal brain. All 20 patient-derived neurospheres showed ubiquitous B7-H3 expression. B7-H3-redirected CAR-T cells effectively targeted GBM cell lines and neurospheres in vitro and in vivo. No significant differences were found between CD28 and 4-1BB co-stimulation, although CD28-co-stimulated CAR-T cells released more inflammatory cytokines. Interpretation: We demonstrated that B7-H3 is highly expressed in GBM specimens and neurospheres that contain putative cancer stem cells, and that B7-H3-redirected CAR-T cells can effectively control tumor growth. Therefore, B7-H3 represents a promising target in GBM. Fund: Alex's Lemonade Stand Foundation; Il Fondo di Gio Onlus; National Cancer Institute; Burroughs Wellcome Fund. Keywords: Glioblastoma, B7-H3, Chimeric antigen receptor, Immunotherapy, Cancer stem cells
