Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia
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 r...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050121001467 |
| _version_ | 1818403868848947200 |
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| author | Scott Raskin Stacey Van Pelt Keri Toner Preethi Bala Balakrishnan Hema Dave Catherine M. Bollard Eric Yvon |
| author_facet | Scott Raskin Stacey Van Pelt Keri Toner Preethi Bala Balakrishnan Hema Dave Catherine M. Bollard Eric Yvon |
| author_sort | Scott Raskin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T08:31:06Z |
| format | Article |
| id | doaj.art-1e9a41f1449c4bdfb967452ebe6ee458 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-14T08:31:06Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-1e9a41f1449c4bdfb967452ebe6ee4582022-12-21T23:09:30ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012021-12-0123296306Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemiaScott Raskin0Stacey Van Pelt1Keri Toner2Preethi Bala Balakrishnan3Hema Dave4Catherine M. Bollard5Eric Yvon6Program for Cell Enhancement and Technologies for Immunotherapy, Children’s National Health System, Washington, DC 20010, USAInstitute for Biomedical Sciences, The George Washington University, Washington, DC 20052, USA; The George Washington University Cancer Center, Washington, DC 20052, USAProgram 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, USAInstitute for Biomedical Sciences, The George Washington University, Washington, DC 20052, USAInstitute for Biomedical Sciences, The George Washington University, Washington, DC 20052, USA; The George Washington University Cancer Center, Washington, DC 20052, USAProgram 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, USAThe 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.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.http://www.sciencedirect.com/science/article/pii/S2329050121001467chimeric antigen receptorCART cell receptor-like antibodyTCR-like antibodycancer-testis antigenCTA |
| spellingShingle | Scott Raskin Stacey Van Pelt Keri Toner Preethi Bala Balakrishnan Hema Dave Catherine M. Bollard Eric Yvon Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia Molecular Therapy: Methods & Clinical Development chimeric antigen receptor CAR T cell receptor-like antibody TCR-like antibody cancer-testis antigen CTA |
| title | Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia |
| title_full | Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia |
| title_fullStr | Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia |
| title_full_unstemmed | Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia |
| title_short | Novel TCR-like CAR-T cells targeting an HLA∗0201-restricted SSX2 epitope display strong activity against acute myeloid leukemia |
| title_sort | novel tcr like car t cells targeting an hla∗0201 restricted ssx2 epitope display strong activity against acute myeloid leukemia |
| topic | chimeric antigen receptor CAR T cell receptor-like antibody TCR-like antibody cancer-testis antigen CTA |
| url | http://www.sciencedirect.com/science/article/pii/S2329050121001467 |
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