Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia

Scott Raskin; Stacey Van Pelt; Keri Toner; Preethi Bala Balakrishnan; Hema Dave; Catherine M. Bollard; Eric Yvon

Molecular Therapy: Methods & Clinical Development (Dec 2021)

Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia

Scott Raskin,
Stacey Van Pelt,
Keri Toner,
Preethi Bala Balakrishnan,
Hema Dave,
Catherine M. Bollard,
Eric Yvon

Affiliations

Scott Raskin: Program for Cell Enhancement and Technologies for Immunotherapy, Children’s National Health System, Washington, DC 20010, USA
Stacey Van Pelt: Institute for Biomedical Sciences, The George Washington University, Washington, DC 20052, USA; The George Washington University Cancer Center, Washington, DC 20052, USA
Keri Toner: Program for Cell Enhancement and Technologies for Immunotherapy, Children’s National Health System, Washington, DC 20010, USA; The George Washington University Cancer Center, Washington, DC 20052, USA
Preethi Bala Balakrishnan: Institute for Biomedical Sciences, The George Washington University, Washington, DC 20052, USA
Hema Dave: Institute for Biomedical Sciences, The George Washington University, Washington, DC 20052, USA; The George Washington University Cancer Center, Washington, DC 20052, USA
Catherine M. Bollard: Program for Cell Enhancement and Technologies for Immunotherapy, Children’s National Health System, Washington, DC 20010, USA; Institute for Biomedical Sciences, The George Washington University, Washington, DC 20052, USA; The George Washington University Cancer Center, Washington, DC 20052, USA
Eric Yvon: The George Washington University Cancer Center, Washington, DC 20052, USA; Department of Medicine, The George Washington University, Washington, DC 20052, USA; Corresponding author: Eric Yvon, PhD, Department of Medicine, The George Washington University, 2150 Pennsylvania Avenue, NW, Washington, DC 20037, USA.

Journal volume & issue: Vol. 23
pp. 296 – 306

Abstract

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Summary: The synovial sarcoma X breakpoint 2 (SSX2) belongs to a multigene family of cancer-testis antigens and can be found overexpressed in multiple malignancies. Its restricted expression in immune-privileged normal tissues suggest that SSX2 may be a relevant target antigen for chimeric antigen receptor (CAR) therapy. We have developed a T cell receptor (TCR)-like antibody (Fab/3) that binds SSX2 peptide 41-49 (KASEKIFYV) in the context of HLA-A∗-0201. The sequence of Fab/3 was utilized to engineer a CAR with the CD3 zeta intra-cellular domain along with either a CD28 or 4-1BB costimulatory endodomain. Human T cells from HLA-A2+ donors were transduced to mediate anti-tumor activity against acute myeloid leukemia (AML) tumor cells. Upon challenge with HLA-A2+/SSX2+ AML tumor cells, CAR-expressing T cells released interferon-γ and eliminated the tumor cells in a long-term co-culture assay. Using the HLA-A2+ T2 cell line, we demonstrated a strong specificity of the single-chain variable fragment (scFv) for SSX2 p41-49 and the closely related SSX3 p41-49, with no response against the others SSX-homologous peptides or unrelated homologous peptides. Since SSX3 has not been observed in tumor cells and expression cannot be induced by pharmacological intervention, SSX241-49 represents an attractive target for CAR-based cellular therapy to treat multiple types of cancer.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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